Pharmaceutical Cream Compositions of Oxymetazoline and Methods of Use

ABSTRACT

The present invention is directed to: a) a method of treating telangiectasia; b) a method of treating inflammatory lesions; and c) a method of treating two or more symptoms of rosacea selected from erythema, telangiectasia, or inflammatory lesions comprising topical administration of a pharmaceutical composition comprising oxymetazoline and a pharmaceutically acceptable excipient.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application Ser.No. 61/443,210, filed Feb. 15, 2011, which is incorporated by referenceherein in its entirety.

BRIEF SUMMARY OF THE INVENTION

Embodiments may include a cream formulation of oxymetazoline.Embodiments may be directed to a cosmetically acceptable formulationcomprising oxymetazoline and a pharmaceutically acceptable excipient,wherein the formulation is a cream. Embodiments may be directed to aformulation comprising oxymetazoline and a pharmaceutically acceptableexcipient, wherein the formulation is a cream. Embodiments may bedirected to a cream formulation comprising oxymetazoline in atherapeutically effective amount and a pharmaceutically acceptableexcipient.

Embodiments may be directed to a method of treating telangiectasiacomprising topical administration of a pharmaceutical compositioncomprising oxymetazoline and a pharmaceutically acceptable excipient. Insome embodiments, a method of treating telangiectasia may comprisetopically administering a pharmaceutical composition comprising atherapeutically effective amount of oxymetazoline and a pharmaceuticallyacceptable excipient. In some embodiments, a method of treatingtelangiectasia may comprise topically administering a pharmaceuticalcomposition comprising a therapeutically effective amount ofoxymetazoline and a pharmaceutically acceptable excipient in combinationwith an additional therapy directed toward the treatment oftelangiectasias in order to provide additional additive or synergisticeffect on the telangiectasias. In some embodiments, a method of treatingtelangiectasia may comprise topically administering a pharmaceuticalcomposition comprising a therapeutically effective amount ofoxymetazoline and a pharmaceutically acceptable excipient in combinationwith an additional therapy directed toward the treatment of theerythema, papules, pustules, phymas, epidermal barrier dysfunction, orother manifestation of rosacea in order to provide treatment of thetelangiectasias.

Embodiments may be directed to a method of treating inflammatory lesionscomprising topical administration of a pharmaceutical compositioncomprising oxymetazoline and a pharmaceutically acceptable excipient. Insome embodiments, a method of treating inflammatory lesions may comprisetopically administering a pharmaceutical composition comprising atherapeutically effective amount of oxymetazoline and a pharmaceuticallyacceptable excipient. In some embodiments, a method of treatinginflammatory lesions may comprise topically administering apharmaceutical composition comprising a therapeutically effective amountof oxymetazoline and a pharmaceutically acceptable excipient incombination with an additional therapy directed toward the treatment ofinflammatory lesions in order to provide additional additive orsynergistic effect on the inflammatory lesions. In some embodiments, amethod of treating inflammatory lesions may comprise topicallyadministering a pharmaceutical composition comprising a therapeuticallyeffective amount of oxymetazoline and a pharmaceutically acceptableexcipient in combination with an additional therapy directed toward thetreatment of noninflammatory manifestations of rosacea such astelangiectasias, erythema, epidermal barrier dysfunction, or othermanifestation of rosacea in order to provide treatment of bothinflammatory and noninflammatory manifestations.

Embodiments may be directed to a method of treating two or more symptomsof rosacea selected from erythema, telangiectasia, or inflammatorylesions comprising topical administration of a pharmaceuticalcomposition comprising oxymetazoline and a pharmaceutically acceptableexcipient. In some embodiments, a method of treating two or moresymptoms of rosacea selected from erythema, telangiectasia, orinflammatory lesions may comprise topically administering apharmaceutical composition comprising a therapeutically effective amountof oxymetazoline and a pharmaceutically acceptable excipient.

Embodiments may be directed to a method of treating erythema,telangiectasia, and inflammatory lesions associated with rosaceacomprising topical administration of a pharmaceutical compositioncomprising oxymetazoline and a pharmaceutically acceptable excipient. Insome embodiments, a method of treating erythema, telangiectasia, andinflammatory lesions associated with rosacea may comprise topicallyadministering a pharmaceutical composition comprising a therapeuticallyeffective amount of oxymetazoline and a pharmaceutically acceptableexcipient.

In some embodiments, the therapeutic effect of cream formulationsdescribed herein may be maintained for at least about 30 days, for atleast 25 days, for at least 20 days, for at least 15 days, for at least10 days after stopping the administration of the cream formulation. Insome embodiments, the therapeutic effect may be maintained for at leastabout 7 days, for at least about 5 days, or for at least about 4 daysafter stopping the administration of the cream formulation.

Embodiments may be directed to a cream formulation comprisingoxymetazoline in an amount of from about 0.0075% to about 5% by weightand pharmaceutically acceptable excipients. In some embodiments, thecream formulation may comprise oxymetazoline in an amount from about0.01% to about 2% by weight. Embodiments may include one or moreemulsifiers in a total amount of from about 1% to about 30% by weight ofthe pharmaceutical composition; and/or one or more emollients in a totalamount of from about 1% to about 50% by weight of the pharmaceuticalcomposition. In some embodiments, the formulation may further compriseadditional additives selected from the group consisting ofpreservatives, emulsifiers, emulsion stabilizers, pH adjusters,chelating agents, viscosity modifiers, anti-oxidants, surfactants,emollients, opacifying agents, skin conditioners, buffers, andcombinations thereof. In some embodiments, the formulation may furthercomprise a topically active pharmaceutical or cosmetic agent.

In certain embodiments, a cream comprising oxymetazoline, avasoconstrictor and pharmaceutically acceptable excipients is provided.In certain embodiments, a cream comprising oxymetazoline, analpha-adrenergic agonist and pharmaceutically acceptable excipients isprovided. In certain embodiments, a cream comprising oxymetazoline, animidazoline alpha-adrenergic agonist and pharmaceutically acceptableexcipients is provided. In certain embodiments, a cream comprisingoxymetazoline, a non-imidazoline alpha-adrenergic agonist andpharmaceutically acceptable excipients is provided. In certainembodiments, a cream comprising oxymetazoline, an alpha-1 adrenergicagonist and pharmaceutically acceptable excipients is provided. Incertain embodiments, a cream comprising oxymetazoline, an alpha-2adrenergic agonist and pharmaceutically acceptable excipients isprovided. In certain embodiments, a cream comprising oxymetazoline, aselective alpha-adrenergic agonist and pharmaceutically acceptableexcipients is provided. In certain embodiments, a cream comprisingoxymetazoline, a non-selective alpha-adrenergic agonist andpharmaceutically acceptable excipients is provided. In certainembodiments, a cream comprising oxymetazoline, a selective alpha-1adrenergic agonist and pharmaceutically acceptable excipients isprovided. In certain embodiments, a cream comprising oxymetazoline, aselective alpha-2 adrenergic agonist and pharmaceutically acceptableexcipients is provided. In certain embodiments, a cream comprisingoxymetazoline, a non-selective alpha-1 adrenergic agonist andpharmaceutically acceptable excipients is provided. In certainembodiments, a cream comprising oxymetazoline, a non-selective alpha-2adrenergic agonist and pharmaceutically acceptable excipients isprovided.

In some embodiments, a method of treating a skin condition, including,but not limited to, rosacea, including, for example,erythematotelangiectatic rosacea, papulopustular rosacea, phymatousrosacea, ocular rosacea or combinations thereof; and symptoms associatedwith rosacea, including, for example, papules, pustules, phymas (skinthickening), telangiectasias or erythema associated with rosacea, otherskin erythemas, telangiectasias, purpura or the like, and othermanifestations associated therewith; other inflammatory conditions ofthe skin including, but not limited to, keratosis pilaris, lupusmiliaris dissemniatus faciei, eczema, dermatitis, such as contactdermatitis, atopic dermatitis, seborrheic dermatitis, nummulardermatitis, generalized exfoliative dermatitis, statis dermatitis,neurodermatitis, lichen simplex chronicus, xerosis and xeroticdermatitis, dyshidrosis and dyshidrotic dermatitis, asteototicdermatitis or other conditions characterized by sensitive skin or adisturbance of the epidermal barrier; disorders characterized by rough,dry, cracked or fissured skin, disorders characterized by hyperkeratoticskin such as keratodermas and ichthyosisis and ichthyosiform dermatoses;disorders of hair follicles and sebaceous glands, such as acne, perioraldermatitis, and pseudofolliculitis barbae; disorders of sweat glands,such as miliaria, including, but not limited to, miliaria crystallina,miliaria rubra, miliaria profunda, miliaria pustulosa; sunburn, chronicactinic damage, poikiloderma, radiation dermatitis, actinic purpura(“solar purpura”); other inflammatory dermatoses, reactions andconditions of the skin, including, but not limited to, psoriasis, drugeruptions, erythema multiforme, erythema nodosum, and granulomaannulare; diseases and conditions characterized by bleeding or bruisingsuch as petechiae, ecchymosis, purpura and the like including anyaccumulation of blood in the skin due to vascular extravasation,irrespective of size or cause, bleeding or bruising due to any skininjury which may include any trauma including surgical or proceduraltrauma; infection, inflammatory dermatoses or inflammation due to anycause or combinations thereof comprising administering a creamformulation of embodiments described herein is provided.

DESCRIPTION OF DRAWINGS

For a fuller understanding of the nature and advantages of embodimentsdescribed herein, reference should be made to the following detaileddescription taken in connection with the accompanying drawings, inwhich:

FIG. 1 is a bar graph showing the mean cosmetic acceptability scoresincluding appearance and sensorial evaluation scores by category forcreams of Trial 36, Trial 2, Trial 11 and Trial 20.

FIG. 2 is a bar graph showing the mean cosmetic acceptability scoresincluding appearance and sensorial evaluation scores for creams of Trial36, Trial 2, Trial 11 and Trial 20 in key categories.

FIG. 3 is a bar graph showing the total mean cosmetic acceptabilityscores including appearance and sensorial evaluation scores for each ofthe creams of Trial 36, Trial 2, Trial 11 and Trial 20.

FIG. 4 illustrates the change from baseline of clinician'stelangiectasia assessment scores at day 28 of the randomized,double-blind, vehicle-controlled, parallel group study.

FIG. 5 illustrates the maintenance of clinical effect at day 35 afterdiscontinuing oxymetazoline cream compositions after 28 days of dailyapplication. The improvement in erythema was maintained for at least 7days after discontinuation of drug application, and there was norebound/worsening of erythema condition.

DETAILED DESCRIPTION

Before the present compositions and methods are described, it is to beunderstood that this invention is not limited to the particularprocesses, compositions, or methodologies described, as these may vary.It is also to be understood that the terminology used in the descriptionis for the purpose of describing the particular versions or embodimentsonly, and is not intended to limit the scope of the present inventionwhich will be limited only by the appended claims. Unless definedotherwise, all technical and scientific terms used herein have the samemeaning as commonly understood by one of ordinary skill in the art.Although any methods and materials similar or equivalent to thosedescribed herein can be used in the practice or testing of embodimentsof the present invention, the preferred methods, devices, and materialsare now described. All publications mentioned herein are incorporated byreference in their entirety. Nothing herein is to be construed as anadmission that the invention is not entitled to antedate such disclosureby virtue of prior invention.

It must also be noted that as used herein and in the appended claims,the singular forms “a”, “an”, and “the” include plural reference unlessthe context clearly dictates otherwise. Thus, for example, reference toa “preservative” is a reference to one or more preservatives andequivalents thereof known to those skilled in the art, and so forth.

As used herein, the term “about” means plus or minus 10% of thenumerical value of the number with which it is being used. Therefore,about 50% means in the range of 45%-55%.

“Administering”, when used in conjunction with a therapeutic, means toadminister a therapeutic directly into or onto a target tissue or toadminister a therapeutic to a subject, whereby the therapeuticpositively impacts the tissue to which it is targeted. Thus, as usedherein, the term “administering”, when used in conjunction with atherapeutic, can include, but is not limited to, providing a therapeuticto a subject systemically by, for example, intravenous injection,whereby the therapeutic reaches the target tissue. Administering acomposition or therapeutic may be accomplished by, for example,injection, oral administration, topical administration, or by thesemethods in combination with other known techniques. Such combinationtechniques may include heating, radiation, ultrasound and the use ofdelivery agents. Preferably, administering is a self-administration,wherein the therapeutic or composition is administered by the subjectthemselves. Alternatively, administering may be administration to thesubject by a health care provider.

“Providing”, when used in conjunction with a therapeutic, means toadminister a therapeutic directly into or onto a target tissue, or toadminister a therapeutic to a subject whereby the therapeutic positivelyimpacts the tissue to which it is targeted.

The term “animal” as used herein includes, but is not limited to, humansand non-human vertebrates such as wild, domestic and farm animals.

The term “patient” or “subject” as used herein is an animal,particularly a human, suffering from an unwanted disease or conditionthat may be treated by the therapeutic and/or compositions describedherein.

The term “improves” is used to convey that the present invention changeseither the characteristics and/or the physical attributes of the tissueto which it is being provided, applied or administered. The term“improves” may also be used in conjunction with a diseased state suchthat when a diseased state is “improved” the symptoms or physicalcharacteristics associated with the diseased state are diminished,reduced or eliminated.

The term “inhibiting” generally refers to prevention of the onset of thesymptoms, alleviating the symptoms, or eliminating the disease,condition or disorder.

“Optional” or “optionally” means that the subsequently described eventor circumstance may or may not occur, and that the description includesinstances where the event occurs and instances where it does not.

As used herein, “room temperature” means an indoor temperature of fromabout 20° C. to about 25° C. (68 to 77° F.).

Throughout the specification of the application, various terms are usedsuch as “primary,” “secondary,” “first,” “second,” and the like. Theseterms are words of convenience in order to distinguish between differentelements, and such terms are not intended to be limiting as to how thedifferent elements may be utilized.

By “pharmaceutically acceptable,” “physiologically tolerable,” andgrammatical variations thereof, as they refer to compositions, carriers,diluents, and reagents or other ingredients of the formulation, can beused interchangeably and represent that the materials are capable ofbeing administered without the production of undesirable physiologicaleffects such as rash, burning, irritation or other deleterious effectsto such a degree as to be intolerable to the recipient thereof.

As used herein, the term “cosmetically acceptable” and grammaticalvariations thereof, as they refer to compositions, carriers, diluents,and reagents or other ingredients of the formulation, represent that thematerials used and final composition are not irritating or otherwiseharmful to the patient in general and to the skin, in particular, andpreferably are pleasant and well tolerated with respect to generalappearance, pH, color, smell and texture (feel), that they are not, forexample, unacceptably sticky (tacky), oily or drying, and that they dospread easily, absorb into the skin at an acceptable rate of absorption,and are generally moisturizing.

“Pharmaceutically acceptable salts” include both acid and base additionsalts. “Pharmaceutically acceptable acid addition salt” refers to thosesalts that retain biological effectiveness and properties of the freebases and that include inorganic acids such as, for example,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,carbonic acid, phosphoric acid, and the like. Organic acids may beselected from aliphatic, cycloaliphatic, aromatic, araliphatic,heterocyclic, carboxylic, and sulfonic classes of organic acids, such asformic acid, acetic acid, propionic acid, glycolic acid, gluconic acid,lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid,maloneic acid, succinic acid, fumaric acid, tartaric acid, citric acid,aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoicacid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicyclic acid, and the like.

As used herein, the term “therapeutic” means an agent utilized to treat,combat, ameliorate, prevent or improve an unwanted condition or diseaseof a subject. In part, embodiments of the present invention are directedto the treatment of various skin diseases, conditions or disorders orsymptoms thereof, including, but not limited to, rosacea and symptomsassociated with rosacea, including, for example, papules, pustules,phymas (skin thickening), telangiectasias or erythema associated withrosacea, other skin erythemas, telangiectasias, purpura or the like, andother manifestations associated therewith; other inflammatory conditionsof the skin including, but not limited to, keratosis pilaris, lupusmiliaris dissemniatus faciei, eczema, dermatitis, such as contactdermatitis, atopic dermatitis, seborrheic dermatitis, nummulardermatitis, generalized exfoliative dermatitis, statis dermatitis,neurodermatitis, lichen simplex chronicus, xerosis and xeroticdermatitis, dyshidrosis and dyshidrotic dermatitis, asteototicdermatitis or other conditions characterized by sensitive skin or adisturbance of the epidermal barrier; disorders characterized by rough,dry, cracked or fissured skin, disorders characterized by hyperkeratoticskin such as keratodermas and ichthyosisis and ichthyosiform dermatoses;disorders of hair follicles and sebaceous glands, such as acne, perioraldermatitis, and pseudofolliculitis barbae; disorders of sweat glands,such as miliaria, including, but not limited to, miliaria crystallina,miliaria rubra, miliaria profunda, miliaria pustulosa; sunburn, chronicactinic damage, poikiloderma, radiation dermatitis, actinic purpura(“solar purpura”); other inflammatory dermatoses, reactions andconditions of the skin, including, but not limited to, psoriasis, drugeruptions, erythema multiforme, erythema nodosum, and granulomaannulare; diseases and conditions characterized by bleeding or bruisingsuch as petechiae, ecchymosis, purpura and the like including anyaccumulation of blood in the skin due to vascular extravasation,irrespective of size or cause, bleeding or bruising due to any skininjury which may include any trauma including surgical or proceduraltrauma; infection, inflammatory dermatoses or inflammation due to anycause or combinations thereof.

The terms “therapeutically effective” or “effective”, as used herein,may be used interchangeably and refer to an amount of a therapeuticcomposition of embodiments of the present invention (e.g., a compositioncomprising oxymetazoline). For example, a therapeutically effectiveamount of a composition is an amount of the composition, andparticularly the active ingredient, such as oxymetazoline, thatgenerally achieves the desired effect.

A “therapeutically effective amount” or “effective amount” of acomposition is an amount necessary or sufficient to achieve the desiredresult. The activity contemplated by the embodiments herein includesmedically therapeutic and/or prophylactic treatment, as appropriate. Thespecific dose of a compound administered according to this invention toobtain therapeutic and/or prophylactic effects will, of course, bedetermined by the particular circumstances surrounding the case,including, for example, the compound administered, the route ofadministration, and the condition being treated. However, the effectiveamount administered can be determined by the practitioner ormanufacturer or patient in light of the relevant circumstances includingthe condition to be treated, the choice of compound to be administered,and the chosen route of administration, and therefore, the above dosageranges are not intended to limit the scope of the invention in any way.A therapeutically effective amount of the compound of embodiments hereinis typically an amount such that when it is administered in aphysiologically tolerable excipient composition, it is sufficient toachieve an effective systemic concentration or local concentration in oron the tissue to achieve the desired therapeutic or clinical outcome.

The terms “treat,” “treated,” or “treating” as used herein refers totherapeutic treatment and/or prophylactic or preventative measures,wherein the object is to prevent or slow down (lessen) an undesiredphysiological condition, disorder or disease, or to obtain beneficial ordesired clinical results. For the purposes of this invention, beneficialor desired clinical results include, but are not limited to, alleviationof symptoms; diminishment of the extent of the condition, disorder ordisease; stabilization (i.e., not worsening) of the state of thecondition, disorder or disease; delay in onset or slowing of theprogression of the condition, disorder or disease; amelioration of thecondition, disorder or disease state; and remission (whether partial ortotal), whether detectable or undetectable, or enhancement orimprovement of the condition, disorder or disease. Treatment includeseliciting a clinically significant response without excessive levels ofside effects.

As used herein, the term “consists of” or “consisting of” means that theformulation includes only the elements, steps, or ingredientsspecifically recited in the particular claimed embodiment or claim.

As used herein, the term “consisting essentially of” or “consistsessentially of” means that the only active pharmaceutical ingredient inthe formulation or method that treats the specified condition (e.g.erythema or redness associated with the particular disease to betreated) is the specifically recited therapeutic in the particularembodiment or claim.

Generally speaking, the term “tissue” refers to any aggregation ofsimilarly specialized cells which are united in the performance of aparticular function.

Rosacea is a chronic disease most commonly characterized by facialerythema (redness). There are at least four identified rosacea subtypesand patients may have more than one subtype present. The four most wellrecognized subtypes are erythematotelangiectatic rosacea (ETR);papulopustular rosacea; phymatous rosacea; and ocular rosacea. Otherless common forms exist and the signs and symptoms of each subtype arenot unique to that subtype and may overlap or coexist with any of themanifestations of any other subtype. ETR may be characterized bytransient and/or permanent erythema with a tendency to flush and blusheasily and telangiectasias, which in its milder form may resemble orpresent as erythema (redness) and in its more pronounced state maymanifest as discrete visible blood vessels on the surface of the skin.Papulopustular rosacea may be characterized by transient and/orpermanent erythema with papules (red bumps) and pustules (pus filledbumps). Without wishing to be bound by theory, though the papules andother inflammatory lesions (e.g. pustules) of papulopustular rosacea maybe mistaken for acne, it is believed that the papules and pustules ofrosacea are different from the papules and pustules of acne and arisefrom different underlying pathophysiologic processes. Phymatous rosaceamay be characterized by thickening skin, irregular surface nodularities,enlargement of facial areas (e.g. nose and cheeks), erythema andtelangiectasias. Ocular rosacea may be characterized by red, dry andirritated eyes and eyelids. In each subtype, erythema andtelangiectasias of varying degree may be a feature.

Rosacea patients may need topical or oral (systemic) medication toalleviate their distress; however, a patient's skin may be so sensitivethat many products are irritating and, in fact, may exacerbate thesymptoms of rosacea and may cause more redness and discomfort thanpatients can tolerate. Thus, rosacea can be very difficult toeffectively treat and thus may not only be physically distressing butalso psychologically distressing. Accordingly, there is a need for acosmetically and pharmaceutically acceptable therapeutic which addressesthe myriad manifestations of rosacea including, but not limited to, theerythema or redness associated with rosacea and the telangiectasiasassociated with rosacea. Additionally, there is a need for acosmetically and pharmaceutically acceptable therapeutic which addressesthe inflammatory lesions and manifestations associated with rosaceaincluding the papules, pustules and phymas (skin thickening).

As used herein, the term “erythema” refers to any redness of the skindue to hyperemia, congestion of the vasculature or dilation of thevasculature of the skin and its surrounding structures. Erythema mayoccur in many conditions of the skin including, but not limited to,rosacea and symptoms associated with rosacea, including, for example,papules, pustules, phymas (skin thickening), telangiectasias or erythemaassociated with rosacea, other skin erythemas, telangiectasias, purpuraor the like, and other manifestations associated therewith; otherinflammatory conditions of the skin including, but not limited to,keratosis pilaris, lupus miliaris dissemniatus faciei, eczema,dermatitis, such as contact dermatitis, atopic dermatitis, seborrheicdermatitis, nummular dermatitis, generalized exfoliative dermatitis,statis dermatitis, neurodermatitis, lichen simplex chronicus, xerosisand xerotic dermatitis, dyshidrosis and dyshidrotic dermatitis,asteototic dermatitis or other conditions characterized by sensitiveskin or a disturbance of the epidermal barrier; disorders characterizedby rough, dry, cracked or fissured skin, disorders characterized byhyperkeratotic skin such as keratodermas and ichthyosisis andichthyosiform dermatoses; disorders of hair follicles and sebaceousglands, such as acne, perioral dermatitis, and pseudofolliculitisbarbae; disorders of sweat glands, such as miliaria, including, but notlimited to, miliaria crystallina, miliaria rubra, miliaria profunda,miliaria pustulosa; sunburn, chronic actinic damage, poikiloderma,radiation dermatitis, actinic purpura (“solar purpura”); otherinflammatory dermatoses, reactions and conditions of the skin,including, but not limited to, psoriasis, drug eruptions, erythemamultiforme, erythema nodosum, and granuloma annulare; diseases andconditions characterized by bleeding or bruising such as petechiae,ecchymosis, purpura and the like including any accumulation of blood inthe skin due to vascular extravasation, irrespective of size or cause,bleeding or bruising due to any skin injury which may include any traumaincluding surgical or procedural trauma; infection, inflammatorydermatoses; inflammation due to any cause or a combination thereof.

Keratosis pilaris (KP) is a very common genetic follicular conditionthat is manifested by the appearance of rough bumps on the skin and maybe accompanied by erythema. Lupus miliaris disseminatus faciei (LMDF) isan uncommon, chronic dermatosis characterized by red-to-yellow oryellow-brown papules of the central face, particularly on and around theeyelids, that may be accompanied by erythema.

As used herein, the term “purpura” refers to any accumulation of bloodin the skin due to vascular extravasation, irrespective of size orcause. As used herein, “purpura” refers to medical conditions commonlyreferred to as “petechiae” (pinpoint spots), “ecchymoses” (largermacular (flat) patches) and “purpura” (larger spots).

Purpura, in general, is hemorrhage of blood out of the vascular spacesand into the skin or surrounding tissues of the skin or mucousmembranes. This hemorrhage results in a collection of blood in thedermis and/or subdermal tissues of the skin that is visible initially asa dark purple/red discoloration that changes color as it breaks down andis resorbed.

In particular, purpura can be characterized as flat (macular ornon-palpable) or raised (palpable or papular). The definition of macularpurpuric subtypes include: petechiae-defined as small purpura (less than4-5 millimeters (mm) in diameter, purpura-defined as greater than 4-5 mmand less than 1 cm (centimeter) in diameter, and ecchymoses-defined asgreater than 1 cm in diameter. The size divisions are not absolute butare useful rules of thumb and there is often a range in size of clinicalpurpuras in any one specific condition.

A bruise, also called a contusion or ecchymosis, is an injury tobiological tissue in which blood vessels such as the capillaries aredamaged, allowing blood to seep into the surrounding tissue(s). Bruisingis usually caused by a blunt impact and its likelihood and its severityincreases as one ages due to thinning and loss of elasticity of theskin.

There exists a need in the art for a topical pharmaceutical compositioncomprising oxymetazoline which is physically stable (i.e. without phaseseparation) and chemically stable with the active pharmaceutical agentand which optimizes the delivery of the oxymetazoline to the skin insuch a manner as to effectively treat the pathologic condition.Therefore, embodiments herein are directed to pharmaceuticalcompositions formulated for topical administration of oxymetazoline. Incertain embodiments, the pharmaceutical compositions may be creams, andsuch creams may have any number and quantity of additional components.Embodiments of the invention are directed at a cream formulationcomprising oxymetazoline from about 0.0075% to about 5% andpharmaceutically acceptable excipients. Embodiments of the invention aredirected at a cream formulation consisting essentially of oxymetazolinefrom about 0.0075% to about 5% and pharmaceutically acceptableexcipients. Embodiments of the invention are directed at a creamformulation consisting of oxymetazoline from about 0.0075% to about 5%and pharmaceutically acceptable excipients. Such formulations may beused to treat rosacea and symptoms associated with rosacea, including,for example, papules, pustules, phymas (skin thickening),telangiectasias or erythema associated with rosacea, other skinerythemas, telangiectasias, purpura or the like, and othermanifestations associated therewith; other inflammatory conditions ofthe skin including, but not limited to, keratosis pilaris, lupusmiliaris dissemniatus faciei, eczema, dermatitis, such as contactdermatitis, atopic dermatitis, seborrheic dermatitis, nummulardermatitis, generalized exfoliative dermatitis, statis dermatitis,neurodermatitis, lichen simplex chronicus, xerosis and xeroticdermatitis, dyshidrosis and dyshidrotic dermatitis, asteototicdermatitis or other conditions characterized by sensitive skin or adisturbance of the epidermal barrier; disorders characterized by rough,dry, cracked or fissured skin, disorders characterized by hyperkeratoticskin such as keratodermas and ichthyosisis and ichthyosiform dermatoses;disorders of hair follicles and sebaceous glands, such as acne, perioraldermatitis, and pseudofolliculitis barbae; disorders of sweat glands,such as miliaria, including, but not limited to, crystallina, miliariarubra, miliaria profunda, miliaria pustulosa; sunburn, chronic actinicdamage, poikiloderma, radiation dermatitis, actinic purpura (“solarpurpura”); other inflammatory dermatoses, reactions and conditions ofthe skin, including, but not limited to, psoriasis, drug eruptions,erythema multiforme, erythema nodosum, and granuloma annulare; diseasesand conditions characterized by bleeding or bruising such as petechiae,ecchymosis, purpura and the like including any accumulation of blood inthe skin due to vascular extravasation, irrespective of size or cause,bleeding or bruising due to any skin injury which may include any traumaincluding surgical or procedural trauma; infection, inflammatorydermatoses, inflammation due to any cause or the like. Such formulationsmay be used to treat or prevent symptoms such as, but not limited to,papules, pustules, other inflammatory lesions, phymas (skin thickening),telangiectasias or erythema associated with rosacea and otherinflammatory conditions of the skin including, but not limited to,keratosis pilaris, lupus miliaris dissemniatus faciei, eczema,dermatitis, such as contact dermatitis, atopic dermatitis, seborrheicdermatitis, nummular dermatitis, generalized exfoliative dermatitis,statis dermatitis, neurodermatitis, lichen simplex chronicus, xerosisand xerotic dermatitis, dyshidrosis and dyshidrotic dermatitis,asteototic dermatitis or other conditions characterized by sensitiveskin or a disturbance of the epidermal barrier; disorders characterizedby rough, dry, cracked or fissured skin, disorders characterized byhyperkeratotic skin such as keratodermas and ichthyosisis andichthyosiform dermatoses; disorders of hair follicles and sebaceousglands, such as acne, perioral dermatitis, and pseudofolliculitisbarbae; disorders of sweat glands, such as miliaria, including, but notlimited to, miliaria crystallina, miliaria rubra, miliaria profunda,miliaria pustulosa; sunburn, chronic actinic damage, poikiloderma,radiation dermatitis, actinic purpura (“solar purpura”); otherinflammatory dermatoses, reactions and conditions of the skin,including, but not limited to, psoriasis, drug eruptions, erythemamultiforme, erythema nodosum, and granuloma annulare; diseases andconditions characterized by bleeding or bruising such as petechiae,ecchymosis, purpura and the like including any accumulation of blood inthe skin due to vascular extravasation, irrespective of size or cause,bleeding or bruising due to any skin injury which may include any traumaincluding surgical or procedural trauma; infection, inflammatorydermatoses or inflammation due to any cause and other skin conditionscharacterized by increased erythema of the skin. Such formulations mayalso be used to treat or prevent purpura, which is a hemorrhage of bloodout of the vascular spaces and into the skin or surrounding tissues ofthe skin or mucous membranes. In further embodiments, the formulation iscosmetically acceptable.

In certain embodiments, as used herein, the term “telangiectasia” refersto a dilation of blood vessels, such as capillaries, arterioles andvenules. In some embodiments, the dilated blood vessels may beclinically indistinguishable. A “clinically indistinguishable bloodvessel” refers to a dilated blood vessel visually indiscernable to anobserver without the aid of magnifying equipment (other than spectaclesnormally used by the observer). In some embodiments, the dilated bloodvessels may be distinguishable. A “distinguishable blood vessel” refersto a dilated blood vessel visually discernable to an observer withoutthe aid of magnifying equipment (other than spectacles normally used bythe observer). In some embodiments, the telangiectasia may be permanent.A permanent telangiectasia may be one that is long-lasting, e.g. wherethe blood vessels remain dilated. In some embodiments, thetelangiectasia may be transient. A transient telangiectasia may be onethat lasts only for a short time or is impermanent. In certainembodiments, telangiectasias may be dilated blood vessels with adiameter of more than or equal to about 0.5 mm. In certain embodiments,telangiectasias may be dilated blood vessels with a diameter of about0.5 mm to about 1 mm. In certain embodiments, telangiectasias may bedilated blood vessels with a diameter of less than about 0.5 mm. Incertain embodiments, telangiectasias may be dilated blood vessels with adiameter of less than about 0.4 mm. In certain embodiments,telangiectasias may be dilated blood vessels with a diameter of lessthan about 0.3 mm. In certain embodiments, telangiectasias may bedilated blood vessels with a diameter of less than about 0.2 mm. Incertain embodiments, telangiectasias may be dilated blood vessels with adiameter of less than about 0.1 mm. Telangiectasias can be associatedwith numerous conditions, syndromes, diseases and disorders. In someaspects, a telangiectasia can be associated with rosacea, while incertain alternative aspects, a telangiectasia can be a telangiectasianot associated with rosacea. In some embodiments, telangiectasia mayinclude any telangiectasia. In some embodiments, a method of treatingtelangiectasia may comprise topical administration of a pharmaceuticalcomposition comprising oxymetazoline and a pharmaceutically acceptableexcipient. In some embodiments, a method of treating telangiectasia maycomprise topically administering a pharmaceutical composition comprisinga therapeutically effective amount of oxymetazoline and apharmaceutically acceptable excipient. In some embodiments, a method oftreating telangiectasia may comprise administering any formulation ofembodiments herein. In some embodiments, the formulation for treatingtelangiectasia may comprise Trial 38 as the base formulation withoxymetazoline in a concentration of from about 0.0075% to about 5% byweight of the cream, including, for example, 0.01%, 0.06%, 0.10%, 0.15%,0.5% or 5%, and pharmaceutically acceptable excipients. In someembodiments, the formulation for treating telangiectasia may consist ofTrial 38 as the base formulation with oxymetazoline in a concentrationof from about 0.0075% to about 5% by weight of the cream, including, forexample, 0.01%, 0.06%, 0.10%, 0.15%, 0.5% or 5%, and pharmaceuticallyacceptable excipients. In some embodiments, the formulation for treatingtelangiectasia may consist essentially of Trial 38 as the baseformulation with oxymetazoline in a concentration of from about 0.0075%to about 5% by weight of the cream, including, for example, 0.01%,0.06%, 0.10%, 0.15%, 0.5% or 5%, and pharmaceutically acceptableexcipients.

In some embodiments, a method of treating inflammatory lesions maycomprise topical administration of a pharmaceutical compositioncomprising oxymetazoline and a pharmaceutically acceptable excipient. Asused herein, “inflammatory lesions” may include papules, pustules, cystsor a combination thereof. In some embodiments, papules may be raisedinflammatory lesions of less than about 0.5 cm in diameter with nopurulent material. In some embodiments, pustules may be raisedinflammatory lesions of less than about 0.5 cm in diameter with visiblepurulent material. In some embodiments, cysts may be any circumscribed,inflammatory mass greater than or equal to about 0.5 cm in diameter. Insome embodiments, a method of treating inflammatory lesions may comprisetopically administering a pharmaceutical composition comprising atherapeutically effective amount of oxymetazoline and a pharmaceuticallyacceptable excipient. In some embodiments, a method of treatinginflammatory lesions may comprise administering any formulation ofembodiments herein. In some embodiments, the formulation for treatinginflammatory lesions may comprise Trial 38 as the base formulation withoxymetazoline in a concentration of from about 0.0075% to about 5% byweight of the cream, including, for example, 0.01%, 0.06%, 0.10%, 0.15%,0.5% or 5%, and pharmaceutically acceptable excipients. In someembodiments, the formulation for treating inflammatory lesions mayconsist of Trial 38 as the base formulation with oxymetazoline in aconcentration of from about 0.0075% to about 5% by weight of the cream,including, for example, 0.01%, 0.06%, 0.10%, 0.15%, 0.5% or 5%, andpharmaceutically acceptable excipients. In some embodiments, theformulation for treating inflammatory lesions may consist essentially ofTrial 38 as the base formulation with oxymetazoline in a concentrationof from about 0.0075% to about 5% by weight of the cream, including, forexample, 0.01%, 0.06%, 0.10%, 0.15%, 0.5% or 5%, and pharmaceuticallyacceptable excipients.

In some embodiments, a method of treating two or more symptoms ofrosacea selected from erythema, telangiectasia, or inflammatory lesionsmay comprise topical administration of a pharmaceutical compositioncomprising oxymetazoline and a pharmaceutically acceptable excipient. Insome embodiments, a method of treating two or more symptoms of rosaceaselected from erythema, telangiectasia, or inflammatory lesions maycomprise topically administering a pharmaceutical composition comprisinga therapeutically effective amount of oxymetazoline and apharmaceutically acceptable excipient. In some embodiments, a method oftreating two or more symptoms of rosacea selected from erythema,telangiectasia, or inflammatory lesions may comprise administering anyformulation of embodiments herein. In some embodiments, thepharmaceutical composition for treating two or more symptoms of rosaceaselected from erythema, telangiectasia, or inflammatory lesions maycomprise Trial 38 as the base formulation with oxymetazoline in aconcentration of from about 0.0075% to about 5% by weight of the cream,including, for example, 0.01%, 0.06%, 0.10%, 0.15%, 0.5% or 5%, andpharmaceutically acceptable excipients. In some embodiments, thepharmaceutical composition for treating two or more symptoms of rosaceaselected from erythema, telangiectasia, or inflammatory lesions mayconsist of Trial 38 as the base formulation with oxymetazoline in aconcentration of from about 0.0075% to about 5% by weight of the cream,including, for example, 0.01%, 0.06%, 0.10%, 0.15%, 0.5% or 5%, andpharmaceutically acceptable excipients. In some embodiments, theformulation for treating two or more symptoms of rosacea selected fromerythema, telangiectasia, or inflammatory lesions may consistessentially of Trial 38 as the base formulation with oxymetazoline in aconcentration of from about 0.0075% to about 5% by weight of the cream,including, for example, 0.01%, 0.06%, 0.10%, 0.15%, 0.5% or 5%, andpharmaceutically acceptable excipients.

In some embodiments, a method of treating erythema, telangiectasia, andinflammatory lesions associated with rosacea may comprise topicaladministration of a pharmaceutical composition comprising oxymetazolineand a pharmaceutically acceptable excipient. In some embodiments, amethod of treating erythema, telangiectasia, and inflammatory lesionsassociated with rosacea may comprise topically administering apharmaceutical composition comprising a therapeutically effective amountof oxymetazoline and a pharmaceutically acceptable excipient. In someembodiments, a method of treating erythema, telangiectasia, andinflammatory lesions associated with rosacea may comprise administeringany formulation of embodiments herein. In some embodiments, thepharmaceutical composition treating erythema, telangiectasia, andinflammatory lesions associated with rosacea may comprise Trial 38 asthe base formulation with oxymetazoline in a concentration of from about0.0075% to about 5% by weight of the cream, including, for example,0.01%, 0.06%, 0.10%, 0.15%, 0.5% or 5%, and pharmaceutically acceptableexcipients. In some embodiments, the pharmaceutical composition fortreating erythema, telangiectasia, and inflammatory lesions associatedwith rosacea may consist of Trial 38 as the base formulation withoxymetazoline in a concentration of from about 0.0075% to about 5% byweight of the cream, including, for example, 0.01%, 0.06%, 0.10%, 0.15%,0.5% or 5%, and pharmaceutically acceptable excipients. In someembodiments, the formulation for treating erythema, telangiectasia, andinflammatory lesions associated with rosacea may consist essentially ofTrial 38 as the base formulation with oxymetazoline in a concentrationof from about 0.0075% to about 5% by weight of the cream, including, forexample, 0.01%, 0.06%, 0.10%, 0.15%, 0.5% or 5%, and pharmaceuticallyacceptable excipients.

Further embodiments are directed to methods of treating erythema,redness or telangiectasias associated with rosacea comprisingadministering a cream comprising oxymetazoline in a therapeuticallyeffective amount. Embodiments are directed to methods of treatingpapules, pustules, and other inflammatory lesions associated withrosacea comprising administering a cream comprising oxymetazoline in atherapeutically effective amount. Embodiments are directed to methods oftreating skin erythema comprising administering a cream comprisingoxymetazoline in a therapeutically effective amount. Embodiments aredirected to methods of treating purpura comprising administering a creamcomprising oxymetazoline in a therapeutically effective amount.Embodiments are directed to methods of treating keratosis pilaris, lupusmiliaris disseminatus faciei or the like comprising administering acream comprising oxymetazoline in a therapeutically effective amount.Embodiments are directed to methods of treating redness or erythemaassociated with rosacea, skin erythemas, telangiectasias, purpura or thelike, and other manifestations associated therewith; other inflammatoryconditions of the skin including, but not limited to, keratosis pilaris,lupus miliaris dissemniatus faciei, eczema, dermatitis, such as contactdermatitis, atopic dermatitis, seborrheic dermatitis, nummulardermatitis, generalized exfoliative dermatitis, statis dermatitis,neurodermatitis, lichen simplex chronicus, xerosis and xeroticdermatitis, dyshidrosis and dyshidrotic dermatitis, asteototicdermatitis or other conditions characterized by sensitive skin or adisturbance of the epidermal barrier; disorders characterized by rough,dry, cracked or fissured skin, disorders characterized by hyperkeratoticskin such as keratodermas and ichthyosisis and ichthyosiform dermatoses;disorders of hair follicles and sebaceous glands, such as acne, perioraldermatitis, and pseudofolliculitis barbae; disorders of sweat glands,such as miliaria, including, but not limited to, miliaria crystallina,miliaria rubra, miliaria profunda, miliaria pustulosa; sunburn, chronicactinic damage, poikiloderma, radiation dermatitis, actinic purpura(“solar purpura”); other inflammatory dermatoses, reactions andconditions of the skin, including, but not limited to, psoriasis, drugeruptions, erythema multiforme, erythema nodosum, and granulomaannulare; diseases and conditions characterized by bleeding or bruisingsuch as petechiae, ecchymosis, purpura and the like including anyaccumulation of blood in the skin due to vascular extravasation,irrespective of size or cause, bleeding or bruising due to any skininjury which may include any trauma including surgical or proceduraltrauma; infection, inflammatory dermatoses, or inflammation due to anycause. In further embodiments, the formulation is cosmeticallyacceptable.

Embodiments of the invention are directed to methods of treatingerythema or redness associated with rosacea comprising administering acream comprising oxymetazoline in an amount from about 0.0075% to about5% by weight of the cream and pharmaceutically acceptable excipients.Embodiments are directed to methods of treating inflammatory lesionsincluding papules and pustules associated with rosacea comprisingadministering a cream comprising oxymetazoline in an amount from about0.0075% to about 5% by weight of the cream and pharmaceuticallyacceptable excipients. Embodiments are directed to methods of treatingskin thickening (phymas) associated with rosacea comprisingadministering a cream comprising oxymetazoline in an amount from about0.0075% to about 5% by weight of the cream and pharmaceuticallyacceptable excipients. Some embodiments of the invention are directed tomethods of treating erythema or redness associated with telangiectasiacomprising administering a cream comprising oxymetazoline in an amountfrom about 0.0075% to about 5% by weight of the cream andpharmaceutically acceptable excipients. Some embodiments of theinvention are directed to methods of treating telangiectasia comprisingadministering a cream comprising oxymetazoline in an amount from about0.0075% to about 5% by weight of the cream and pharmaceuticallyacceptable excipients. Some embodiments of the invention are directed tomethods of treating erythema or redness associated witherythemato-telangiectatic rosacea comprising administering a creamcomprising oxymetazoline in an amount from about 0.0075% to about 5% byweight of the cream. Some embodiments of the invention are directed tomethods of treating erythemato-telangiectatic rosacea comprisingadministering a cream comprising oxymetazoline in an amount from about0.0075% to about 5% by weight of the cream and pharmaceuticallyacceptable excipients. Some embodiments of the invention are directed tomethods of treating erythema or redness associated with papulopustularrosacea comprising administering a cream comprising oxymetazoline in anamount from about 0.0075% to about 5% by weight of the cream. Someembodiments of the invention are directed to methods of treating papulesassociated with papulopustular rosacea comprising administering a creamcomprising oxymetazoline in an amount from about 0.0075% to about 5% byweight of the cream. Some embodiments of the invention are directed tomethods of treating papulopustular rosacea comprising administering acream comprising oxymetazoline in an amount from about 0.0075% to about5% by weight of the cream and pharmaceutically acceptable excipients.Embodiments of the invention are directed to methods of treatingsymptoms associated with rosacea comprising administering a creamcomprising oxymetazoline in an amount from about 0.0075% to about 5% byweight of the cream and pharmaceutically acceptable excipients, whereinthe symptoms are selected from the group consisting of papules,pustules, erythema (redness), skin thickening and telangiectasias. Someembodiments of the invention are directed to methods of treating purpuracomprising administering a cream comprising oxymetazoline in an amountfrom about 0.0075% to about 5% by weight of the cream andpharmaceutically acceptable excipients. Embodiments are directed tomethods of treating keratosis pilaris, lupus miliaris disseminatusfaciei or the like comprising administering a cream comprisingoxymetazoline in an amount from about 0.0075% to about 5% by weight ofthe cream and pharmaceutically acceptable excipients. Embodiments aredirected to methods of treating rosacea and symptoms associated withrosacea, including, for example, papules, pustules, phymas (skinthickening), telangiectasias or erythema associated with rosacea, otherskin erythemas, telangiectasias, purpura or the like, and othermanifestations associated therewith; other inflammatory conditions ofthe skin including, but not limited to, keratosis pilaris, lupusmiliaris dissemniatus faciei, eczema, dermatitis, such as contactdermatitis, atopic dermatitis, seborrheic dermatitis, nummulardermatitis, generalized exfoliative dermatitis, statis dermatitis,neurodermatitis, lichen simplex chronicus, xerosis and xeroticdermatitis, dyshidrosis and dyshidrotic dermatitis, asteototicdermatitis or other conditions characterized by sensitive skin or adisturbance of the epidermal barrier; disorders characterized by rough,dry, cracked or fissured skin, disorders characterized by hyperkeratoticskin such as keratodermas and ichthyosisis and ichthyosiform dermatoses;disorders of hair follicles and sebaceous glands, such as acne, perioraldermatitis, and pseudofolliculitis barbae; disorders of sweat glands,such as miliaria, including, but not limited to, miliaria crystallina,miliaria rubra, miliaria profunda, miliaria pustulosa; sunburn, chronicactinic damage, poikiloderma, radiation dermatitis, actinic purpura(“solar purpura”); other inflammatory dermatoses, reactions andconditions of the skin, including, but not limited to, psoriasis, drugeruptions, erythema multiforme, erythema nodosum, and granulomaannulare; diseases and conditions characterized by bleeding or bruisingsuch as petechiae, ecchymosis, purpura and the like including anyaccumulation of blood in the skin due to vascular extravasation,irrespective of size or cause, bleeding or bruising due to any skininjury which may include any trauma including surgical or proceduraltrauma; infection, inflammatory dermatoses, inflammation due to anycause comprising administering a cream comprising oxymetazoline in anamount from about 0.0075% to about 5% by weight of the cream andpharmaceutically acceptable excipients. In further embodiments, theformulation is cosmetically acceptable.

Embodiments of the invention are directed to methods of treatingerythema or redness associated with rosacea comprising administering acream consisting of oxymetazoline in an amount from about 0.0075% toabout 5% by weight of the cream and pharmaceutically acceptableexcipients. Embodiments are directed to methods of treating papulesassociated with rosacea comprising administering a cream consisting ofoxymetazoline in an amount from about 0.0075% to about 5% by weight ofthe cream and pharmaceutically acceptable excipients. Embodiments of theinvention are directed to methods of treating symptoms associated withrosacea comprising administering a cream consisting of oxymetazoline inan amount from about 0.0075% to about 5% by weight of the cream andpharmaceutically acceptable excipients, wherein the symptoms areselected from the group consisting of papules, pustules, erythema(redness), skin thickening, and telangiectasias. Some embodiments of theinvention are directed to methods of treating erythema or rednessassociated with telangiectasia comprising administering a creamconsisting of oxymetazoline in an amount from about 0.0075% to about 5%by weight of the cream and pharmaceutically acceptable excipients. Someembodiments of the invention are directed to methods of treatingtelangiectasia comprising administering a cream consisting ofoxymetazoline in an amount from about 0.0075% to about 5% by weight ofthe cream and pharmaceutically acceptable excipients. Some embodimentsof the invention are directed to methods of treating erythema or rednessassociated with erythemato-telangiectatic rosacea comprisingadministering a cream consisting of oxymetazoline in an amount fromabout 0.0075% to about 5% by weight of the cream and pharmaceuticallyacceptable excipients. Some embodiments of the invention are directed tomethods of treating erythemato-telangiectatic rosacea comprisingadministering a cream consisting of oxymetazoline in an amount fromabout 0.0075% to about 5% by weight of the cream and pharmaceuticallyacceptable excipients. Some embodiments of the invention are directed tomethods of treating erythema or redness associated with papulopustularrosacea comprising administering a cream consisting of oxymetazoline inan amount from about 0.0075% to about 5% by weight of the cream. Someembodiments of the invention are directed to methods of treating papulesor pustules associated with papulopustular rosacea comprisingadministering a cream consisting of oxymetazoline in an amount fromabout 0.0075% to about 5% by weight of the cream. Some embodiments ofthe invention are directed to methods of treating papulopustular rosaceacomprising administering a cream consisting of oxymetazoline in anamount from about 0.0075% to about 5% by weight of the cream andpharmaceutically acceptable excipients. Some embodiments of theinvention are directed to methods of treating purpura comprisingadministering a cream consisting of oxymetazoline in an amount fromabout 0.0075% to about 5% by weight of the cream and pharmaceuticallyacceptable excipients. Embodiments are directed to methods of treatingrosacea and symptoms associated with rosacea, including, for example,papules, pustules, phymas (skin thickening), telangiectasias or erythemaassociated with rosacea, other skin erythemas, telangiectasias, purpuraor the like, and other manifestations associated therewith; otherinflammatory conditions of the skin including, but not limited to,keratosis pilaris, lupus miliaris dissemniatus faciei, eczema,dermatitis, such as contact dermatitis, atopic dermatitis, seborrheicdermatitis, nummular dermatitis, generalized exfoliative dermatitis,statis dermatitis, neurodermatitis, lichen simplex chronicus, xerosisand xerotic dermatitis, dyshidrosis and dyshidrotic dermatitis,asteototic dermatitis or other conditions characterized by sensitiveskin or a disturbance of the epidermal barrier; disorders characterizedby rough, dry, cracked or fissured skin, disorders characterized byhyperkeratotic skin such as keratodermas and ichthyosisis andichthyosiform dermatoses; disorders of hair follicles and sebaceousglands, such as acne, perioral dermatitis, and pseudofolliculitisbarbae; disorders of sweat glands, such as miliaria, including, but notlimited to, miliaria crystallina, miliaria rubra, miliaria profunda,miliaria pustulosa; sunburn, chronic actinic damage, poikiloderma,radiation dermatitis, actinic purpura (“solar purpura”); otherinflammatory dermatoses, reactions and conditions of the skin,including, but not limited to, psoriasis, drug eruptions, erythemamultiforme, erythema nodosum, and granuloma annulare; diseases andconditions characterized by bleeding or bruising such as petechiae,ecchymosis, purpura and the like including any accumulation of blood inthe skin due to vascular extravasation, irrespective of size or cause,bleeding or bruising due to any skin injury which may include any traumaincluding surgical or procedural trauma; infection, inflammatorydermatoses, inflammation due to any cause comprising administering acream consisting of oxymetazoline in an amount from about 0.0075% toabout 5% by weight of the cream and pharmaceutically acceptableexcipients. In further embodiments, the formulation is cosmeticallyacceptable.

Embodiments of the invention are directed to methods of treatingerythema or redness associated with rosacea comprising administering acream consisting essentially of oxymetazoline in an amount from about0.0075% to about 5% by weight of the cream and pharmaceuticallyacceptable excipients. Embodiments are directed to methods of treatingpapules associated with rosacea comprising administering a creamconsisting essentially of oxymetazoline in an amount from about 0.0075%to about 5% by weight of the cream and pharmaceutically acceptableexcipients. Embodiments of the invention are directed to methods oftreating symptoms associated with rosacea comprising administering acream consisting essentially of oxymetazoline in an amount from about0.0075% to about 5% by weight of the cream and pharmaceuticallyacceptable excipients, wherein the symptoms are selected from the groupconsisting of papules, pustules, erythema (redness), skin thickening,and telangiectasias. Some embodiments of the invention are directed tomethods of treating erythema or redness associated with telangiectasiacomprising administering a cream consisting essentially of oxymetazolinein an amount from about 0.0075% to about 5% by weight of the cream andpharmaceutically acceptable excipients. Some embodiments of theinvention are directed to methods of treating telangiectasia comprisingadministering a cream consisting essentially of oxymetazoline in anamount from about 0.0075% to about 5% by weight of the cream andpharmaceutically acceptable excipients. Some embodiments of theinvention are directed to methods of treating erythema or rednessassociated with erythemato-telangiectatic rosacea comprisingadministering a cream consisting essentially of oxymetazoline in anamount from about 0.0075% to about 5% by weight of the cream andpharmaceutically acceptable excipients. Some embodiments of theinvention are directed to methods of treating erythemato-telangiectaticrosacea comprising administering a cream consisting essentially ofoxymetazoline in an amount from about 0.0075% to about 5% by weight ofthe cream and pharmaceutically acceptable excipients. Some embodimentsof the invention are directed to methods of treating erythema or rednessassociated with papulopustular rosacea comprising administering a creamconsisting essentially of oxymetazoline in an amount from about 0.0075%to about 5% by weight of the cream. Some embodiments of the inventionare directed to methods of treating papules or pustules associated withpapulopustular rosacea comprising administering a cream consistingessentially of oxymetazoline in an amount from about 0.0075% to about 5%by weight of the cream. Some embodiments of the invention are directedto methods of treating papulopustular rosacea comprising administering acream consisting essentially of oxymetazoline in an amount from about0.0075% to about 5% by weight of the cream and pharmaceuticallyacceptable excipients. Some embodiments of the invention are directed tomethods of treating purpura comprising administering a cream consistingessentially of oxymetazoline in an amount from about 0.0075% to about 5%by weight of the cream and pharmaceutically acceptable excipients.Embodiments are directed to methods of treating keratosis pilaris, lupusmiliaris disseminatus faciei or the like comprising administering acream consisting essentially of oxymetazoline in an amount from about0.0075% to about 5% by weight of the cream and pharmaceuticallyacceptable excipients. Embodiments are directed to methods of treatingrosacea and symptoms associated with rosacea, including, for example,papules, pustules, phymas (skin thickening), telangiectasias or erythemaassociated with rosacea, other skin erythemas, telangiectasias, purpuraor the like, and other manifestations associated therewith; otherinflammatory conditions of the skin including, but not limited to,keratosis pilaris, lupus miliaris dissemniatus faciei, eczema,dermatitis, such as contact dermatitis, atopic dermatitis, seborrheicdermatitis, nummular dermatitis, generalized exfoliative dermatitis,statis dermatitis, neurodermatitis, lichen simplex chronicus, xerosisand xerotic dermatitis, dyshidrosis and dyshidrotic dermatitis,asteototic dermatitis or other conditions characterized by sensitiveskin or a disturbance of the epidermal barrier; disorders characterizedby rough, dry, cracked or fissured skin, disorders characterized byhyperkeratotic skin such as keratodermas and ichthyosisis andichthyosiform dermatoses; disorders of hair follicles and sebaceousglands, such as acne, perioral dermatitis, and pseudofolliculitisbarbae; disorders of sweat glands, such as miliaria, including, but notlimited to, miliaria crystallina, miliaria rubra, miliaria profunda,miliaria pustulosa; sunburn, chronic actinic damage, poikiloderma,radiation dermatitis, actinic purpura (“solar purpura”); otherinflammatory dermatoses, reactions and conditions of the skin,including, but not limited to, psoriasis, drug eruptions, erythemamultiforme, erythema nodosum, and granuloma annulare; diseases andconditions characterized by bleeding or bruising such as petechiae,ecchymosis, purpura and the like including any accumulation of blood inthe skin due to vascular extravasation, irrespective of size or cause,bleeding or bruising due to any skin injury which may include any traumaincluding surgical or procedural trauma; infection, inflammatorydermatoses, inflammation due to any cause comprising administering acream consisting essentially of oxymetazoline in an amount from about0.0075% to about 5% by weight of the cream and pharmaceuticallyacceptable excipients. In further embodiments, the formulation iscosmetically acceptable.

Oxymetazoline is the common name for3-(4,5-dihydro-1H-imidazol-2-ylmethyl)-2,4-dimethyl-6-tert-butyl-phenol,which has the chemical structure:

As used herein, oxymetazoline includes both oxymetazoline free base andan acid addition salt of oxymetazoline. For example, in someembodiments, the oxymetazoline used in the preparation of thepharmaceutical composition may include a pharmaceutical salt, such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,carbonic acid, phosphoric acid, and the like, or an organic acid such asformic acid, acetic acid, propionic acid, glycolic acid, gluconic acid,lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid,maloneic acid, succinic acid, fumaric acid, tartaric acid, citric acid,aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoicacid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicyclic acid, and the like. In certain embodiments, thepharmaceutical salt may be hydrochloric acid

A “cream,” as used herein, refers to a semi-solid emulsion, i.e. adispersed system having at least two immiscible phases where one phaseis dispersed in another, with droplets ranging in diameter from about0.1 μm to about 100 μm that is capable of penetrating the stratumcorneum layer of skin. The creams of various embodiments can have aviscosity of from about 2,500 centipoises (cP) to about 150,000 cP atabout 25° C. In some embodiments, the creams described herein canexhibit a melting point of greater than about 25° C., greater than about30° C., greater than about 35° C., greater than about 40° C., from about25° C. to about 80° C., from about 25° C. to about 60° C., from about30° C. to about 80° C., from about 30° C. to about 60° C., from about35° C. to about 80° C., from about 35° C. to about 60° C., from about35° C. to about 50° C., from about 35° C. to about 40° C., from about40° C. to about 80° C., or from about 40° C. to about 60° C.

In embodiments, a cream comprising oxymetazoline, as the activepharmaceutical ingredient (API), and pharmaceutically acceptableexcipients is provided. In some embodiments, the cream may comprise fromabout 0.0075% to about 5%, from about 0.0075% to about 2.5%, from about0.0075% to about 2%, from about 0.0075% to about 1%, from about 0.0075%to about 0.5%, from about 0.0075% to about 0.25%, from about 0.0075% toabout 0.15%, from about 0.0075% to about 0.1%, from about 0.0075% toabout 0.025%, from about 0.0075% to about 0.075%, from about 0.0075% toabout 0.06%, from about 0.0075% to about 0.05%, from about 0.01% toabout 5%, from about 0.01% to about 2.5%, from about 0.01% to about 2%,from about 0.01% to about 1%, from about 0.01% to about 0.5%, from about0.01% to about 0.25%, from about 0.01% to about 0.15%, from about 0.01%to about 0.1%, from about 0.01% to about 0.025%, from about 0.05% toabout 5%, from about 0.05% to about 2.5%, from about 0.05% to about 2%,from about 0.05% to about 1%, from about 0.05% to about 0.5%, from about0.05% to about 0.25%, from about 0.05% to about 0.15%, from about 0.05%to about 0.1%, from about 0.05% to about 0.075% from about 0.1% to about5%, from about 0.1% to about 2.5%, from about 0.1% to about 2%, fromabout 0.1% to about 1%, from about 0.1% to about 0.5%, from about 0.1%to about 0.25%, from about 0.1% to about 0.15%, from about 0.15% toabout 5%, from about 0.15% to about 2.5%, from about 0.15% to about 2%,from about 0.15% to about 1%, from about 0.15% to about 0.5%, from about0.15% to about 0.25% by weight of oxymetazoline and pharmaceuticallyacceptable excipients. In some embodiments, the cream may comprise about0.0075%, about 0.01%, about 0.025%, about 0.05%, about 0.06%, about0.075%, about 0.1%, about 0.15%, about 0.2%, about 0.25%, about 0.3%,about 0.35%, about 0.4%, about 0.45%, about 0.5%, about 0.75%, about 1%,about 2%, about 2.5% or about 5% by weight of oxymetazoline andpharmaceutically acceptable excipients. In some embodiments, the creammay comprise less than about 5% by weight of oxymetazoline andpharmaceutically acceptable excipients. In some embodiments, the creammay comprise less than about 2.5% by weight of oxymetazoline andpharmaceutically acceptable excipients. In some embodiments, the creammay comprise less than about 2% by weight of oxymetazoline andpharmaceutically acceptable excipients. In some embodiments, the creammay comprise less than about 1% by weight of oxymetazoline andpharmaceutically acceptable excipients. In certain embodiments, a creamcomprising oxymetazoline, a vasoconstrictor and pharmaceuticallyacceptable excipients is provided. In certain embodiments, a creamcomprising oxymetazoline, an alpha-adrenergic agonist andpharmaceutically acceptable excipients is provided. In certainembodiments, a cream comprising oxymetazoline, an imidazolinealpha-adrenergic agonist and pharmaceutically acceptable excipients isprovided. In certain embodiments, a cream comprising oxymetazoline, anon-imidazoline alpha-adrenergic agonist and pharmaceutically acceptableexcipients is provided. In certain embodiments, a cream comprisingoxymetazoline, an alpha-1 adrenergic agonist and pharmaceuticallyacceptable excipients is provided. In certain embodiments, a creamcomprising oxymetazoline, an alpha-2 adrenergic agonist andpharmaceutically acceptable excipients is provided. In certainembodiments, a cream comprising oxymetazoline, a selectivealpha-adrenergic agonist and pharmaceutically acceptable excipients isprovided. In certain embodiments, a cream comprising oxymetazoline, anon-selective alpha-adrenergic agonist and pharmaceutically acceptableexcipients is provided. In certain embodiments, a cream comprisingoxymetazoline, a selective alpha-1 adrenergic agonist andpharmaceutically acceptable excipients is provided. In certainembodiments, a cream comprising oxymetazoline, a selective alpha-2adrenergic agonist and pharmaceutically acceptable excipients isprovided. In certain embodiments, a cream comprising oxymetazoline, anon-selective alpha-1 adrenergic agonist and pharmaceutically acceptableexcipients is provided. In certain embodiments, a cream comprisingoxymetazoline, a non-selective alpha-2 adrenergic agonist andpharmaceutically acceptable excipients is provided.

In embodiments of the present invention a cream consisting essentiallyof oxymetazoline and pharmaceutically acceptable excipients is provided.In some embodiments, the cream may consist essentially of from about0.0075% to about 5%, from about 0.0075% to about 2.5%, from about0.0075% to about 2%, from about 0.0075% to about 1%, from about 0.0075%to about 0.5%, from about 0.0075% to about 0.25%, from about 0.0075% toabout 0.15%, from about 0.0075% to about 0.1%, from about 0.0075% toabout 0.025%, from about 0.0075% to about 0.075%, from about 0.0075% toabout 0.06%, from about 0.0075% to about 0.05%, from about 0.01% toabout 5%, from about 0.01% to about 2.5%, from about 0.01% to about 2%,from about 0.01% to about 1%, from about 0.01% to about 0.5%, from about0.01% to about 0.25%, from about 0.01% to about 0.15%, from about 0.01%to about 0.1%, from about 0.01% to about 0.025%, from about 0.05% toabout 5%, from about 0.05% to about 2.5%, from about 0.05% to about 2%,from about 0.05% to about 1%, from about 0.05% to about 0.5%, from about0.05% to about 0.25%, from about 0.05% to about 0.15%, from about 0.05%to about 0.1%, from about 0.05% to about 0.075% from about 0.1% to about5%, from about 0.1% to about 2.5%, from about 0.1% to about 2%, fromabout 0.1% to about 1%, from about 0.1% to about 0.5%, from about 0.1%to about 0.25%, from about 0.1% to about 0.15%, from about 0.15% toabout 5%, from about 0.15% to about 2.5%, from about 0.15% to about 2%,from about 0.15% to about 1%, from about 0.15% to about 0.5%, from about0.15% to about 0.25% by weight of oxymetazoline and pharmaceuticallyacceptable excipients. In some embodiments, the cream may consistessentially of about 0.0075%, about 0.01%, about 0.025%, about 0.05%,about 0.06%, about 0.075%, about 0.1%, about 0.15%, about 0.2%, about0.25%, about 0.3%, about 0.35%, about 0.4%, about 0.45%, about 0.5%,about 0.75%, about 1%, about 2%, about 2.5% or about 5% by weight ofoxymetazoline and pharmaceutically acceptable excipients. In someembodiments, the cream may consist essentially of less than about 5% byweight of oxymetazoline and pharmaceutically acceptable excipients. Insome embodiments, the cream may consist essentially of less than about2.5% by weight of oxymetazoline and pharmaceutically acceptableexcipients. In some embodiments, the cream may consist essentially ofless than about 2% by weight of oxymetazoline and pharmaceuticallyacceptable excipients. In some embodiments, the cream may consistessentially of less than about 1% by weight of oxymetazoline andpharmaceutically acceptable excipients. In certain embodiments, a creamconsisting essentially of oxymetazoline, a vasoconstrictor andpharmaceutically acceptable excipients is provided. In certainembodiments, a cream consisting essentially of oxymetazoline, analpha-adrenergic agonist and pharmaceutically acceptable excipients isprovided. In certain embodiments, a cream consisting essentially ofoxymetazoline, an imidazoline alpha-adrenergic agonist andpharmaceutically acceptable excipients is provided. In certainembodiments, a cream consisting essentially of oxymetazoline, anon-imidazoline alpha-adrenergic agonist and pharmaceutically acceptableexcipients is provided. In certain embodiments, a cream consistingessentially of oxymetazoline, an alpha-1 adrenergic agonist andpharmaceutically acceptable excipients is provided. In certainembodiments, a cream consisting essentially of oxymetazoline, an alpha-2adrenergic agonist and pharmaceutically acceptable excipients isprovided. In certain embodiments, a cream consisting essentially ofoxymetazoline, a selective alpha-adrenergic agonist and pharmaceuticallyacceptable excipients is provided. In certain embodiments, a creamconsisting essentially of oxymetazoline, a non-selectivealpha-adrenergic agonist and pharmaceutically acceptable excipients isprovided. In certain embodiments, a cream consisting essentially ofoxymetazoline, a selective alpha-1 adrenergic agonist andpharmaceutically acceptable excipients is provided. In certainembodiments, a cream consisting essentially of oxymetazoline, aselective alpha-2 adrenergic agonist and pharmaceutically acceptableexcipients is provided. In certain embodiments, a cream consistingessentially of oxymetazoline, a non-selective alpha-1 adrenergic agonistand pharmaceutically acceptable excipients is provided. In certainembodiments, a cream consisting essentially of oxymetazoline, anon-selective alpha-2 adrenergic agonist and pharmaceutically acceptableexcipients is provided.

In embodiments of the present invention a cream consisting ofoxymetazoline and pharmaceutically acceptable excipients is provided. Insome embodiments, the cream may consist of from about 0.0075% to about5%, from about 0.0075% to about 2.5%, from about 0.0075% to about 2%,from about 0.0075% to about 1%, from about 0.0075% to about 0.5%, fromabout 0.0075% to about 0.25%, from about 0.0075% to about 0.15%, fromabout 0.0075% to about 0.1%, from about 0.0075% to about 0.025%, fromabout 0.0075% to about 0.075%, from about 0.0075% to about 0.06%, fromabout 0.0075% to about 0.05%, from about 0.01% to about 5%, from about0.01% to about 2.5%, from about 0.01% to about 2%, from about 0.01% toabout 1%, from about 0.01% to about 0.5%, from about 0.01% to about0.25%, from about 0.01% to about 0.15%, from about 0.01% to about 0.1%,from about 0.01% to about 0.025%, from about 0.05% to about 5%, fromabout 0.05% to about 2.5%, from about 0.05% to about 2%, from about0.05% to about 1%, from about 0.05% to about 0.5%, from about 0.05% toabout 0.25%, from about 0.05% to about 0.15%, from about 0.05% to about0.1%, from about 0.05% to about 0.075% from about 0.1% to about 5%, fromabout 0.1% to about 2.5%, from about 0.1% to about 2%, from about 0.1%to about 1%, from about 0.1% to about 0.5%, from about 0.1% to about0.25%, from about 0.1% to about 0.15%, from about 0.15% to about 5%,from about 0.15% to about 2.5%, from about 0.15% to about 2%, from about0.15% to about 1%, from about 0.15% to about 0.5%, from about 0.15% toabout 0.25% by weight of oxymetazoline and pharmaceutically acceptableexcipients. In some embodiments, the cream may consist of about 0.0075%,about 0.01%, about 0.025%, about 0.05%, about 0.06%, about 0.075%, about0.1%, about 0.15%, about 0.2%, about 0.25%, about 0.3%, about 0.35%,about 0.4%, about 0.45%, about 0.5%, about 0.75%, about 1%, about 2%,about 2.5% or about 5% by weight of oxymetazoline and pharmaceuticallyacceptable excipients. In some embodiments, the cream may consist ofless than about 5% by weight of oxymetazoline and pharmaceuticallyacceptable excipients. In some embodiments, the cream may consist ofless than about 2.5% by weight of oxymetazoline and pharmaceuticallyacceptable excipients. In some embodiments, the cream may consist ofless than about 2% by weight of oxymetazoline and pharmaceuticallyacceptable excipients. In some embodiments, the cream may consist ofless than about 1% by weight of oxymetazoline and pharmaceuticallyacceptable excipients. In certain embodiments, a cream consisting ofoxymetazoline, a vasoconstrictor and pharmaceutically acceptableexcipients is provided. In certain embodiments, a cream consisting ofoxymetazoline, an adrenomimetic and pharmaceutically acceptableexcipients is provided. In certain embodiments, a cream consisting ofoxymetazoline, an alpha-adrenergic agonist and pharmaceuticallyacceptable excipients is provided. In certain embodiments, a creamconsisting of oxymetazoline, an imidazoline alpha-adrenergic agonist andpharmaceutically acceptable excipients is provided. In certainembodiments, a cream consisting of oxymetazoline, a non-imidazolinealpha-adrenergic agonist and pharmaceutically acceptable excipients isprovided. In certain embodiments, a cream consisting of oxymetazoline,an alpha-1 adrenergic agonist and pharmaceutically acceptable excipientsis provided. In certain embodiments, a cream consisting ofoxymetazoline, an alpha-2 adrenergic agonist and pharmaceuticallyacceptable excipients is provided. In certain embodiments, a creamconsisting of oxymetazoline, a selective alpha-adrenergic agonist andpharmaceutically acceptable excipients is provided. In certainembodiments, a cream consisting of oxymetazoline, a non-selectivealpha-adrenergic agonist and pharmaceutically acceptable excipients isprovided. In certain embodiments, a cream consisting of oxymetazoline, aselective alpha-1 adrenergic agonist and pharmaceutically acceptableexcipients is provided. In certain embodiments, a cream consisting ofoxymetazoline, a selective alpha-2 adrenergic agonist andpharmaceutically acceptable excipients is provided. In certainembodiments, a cream consisting of oxymetazoline, a non-selectivealpha-1 adrenergic agonist and pharmaceutically acceptable excipients isprovided. In certain embodiments, a cream consisting of oxymetazoline, anon-selective alpha-2 adrenergic agonist and pharmaceutically acceptableexcipients is provided.

In an embodiment, the cream may comprise a formulation having a buffersystem. In an embodiment, the cream may comprise a buffering agent. Insome embodiments, the buffering agent may be selected from a groupconsisting of citric acid, sodium citrate, sodium lactate, ammoniumhydroxide, trizma acetate, sodium borate, acetic acid, sodium acetate,phosphoric acid, sodium phosphate, sodium citrate dehydrate and thelike.

In an embodiment of the present invention, the cream may comprise theformulation of any of Trials 22, 24, 25, or 35-51 as described herein.In one embodiment of the present invention, the cream consistsessentially of the formulation of any of Trials 22, 24, 25, or 35-51 asdescribed herein. In one embodiment of the present invention, the creamconsists of the formulation of any of Trials 22, 24, 25, or 35-51 asdescribed herein. In an embodiment of the present invention, the creammay comprise the formulation of Trial 38 as the base formulation withoxymetazoline and a pharmaceutically acceptable excipient as describedherein. In one embodiment of the present invention, the cream consistsessentially of the formulation of Trial 38 as the base formulation withoxymetazoline and a pharmaceutically acceptable excipient as describedherein. In one embodiment of the present invention, the cream consistsof the formulation of Trial 38 as the base formulation withoxymetazoline and a pharmaceutically acceptable excipient as describedherein. In such embodiments, oxymetazoline may be present at aconcentration of from about 0.0075% to about 5% by weight of the cream.

In some embodiments, the oxymetazoline cream may include an emulsifyingagent, or emulsifier. The emulsifier can be provided to adjust theproperties of the cream, such as density, viscosity, the melting point,and/or droplet size; and in some embodiments, the emulsifier mayincrease the stability of the cream. Various emulsions suitable forembodiments described herein and methods for preparing such emulsionsare well known in the art and are described in, for example, Remington'sPharmaceutical Sciences, Mack Publishing Co., Easton, Pa., USA, which ishereby incorporated by reference in its entirety. In some embodiments,the cream may include an emulsifier in an amount from about 1% to about30%, from about 1% to about 25%, from about 1% to about 20%, or fromabout 4% to about 12% emulsifier. In some embodiments, the cream mayinclude emulsifier in an amount greater than 8%. In some embodiments,the cream may include from about 8% to about 30% emulsifier. In someembodiments, the cream may include from about 8% to about 25%emulsifier. In other embodiments, the cream may include from about 8% toabout 20% emulsifier. In still other embodiments, the cream may includefrom about 8% to about 10% emulsifier. If more than one emulsifier isused, the cream may include from about 1% to about 30% of eachemulsifier, from about 2% to about 30% of each emulsifier or from about2% to about 25% of each emulsifier.

The creams of various embodiments may include any emulsifiers orcombination of emulsifiers. For example, in some embodiments, the creammay be a common oil-in-water or water-in-oil emulsion includingoxymetazoline and water or one or more common oils such as, for example,cottonseed, groundnut, corn, germ, olive, castor, soybean, mineral, andsesame oils. In other embodiments, the cream may include one or moreemulsifiers, such as, for example, sesquioleates such as sorbitansesquioleate or polyglyceryl-2-sesquioleate, ethoxylated esters ofderivatives of natural oils such as the polyethoxylated ester ofhydrogenated castor oil, silicone emulsifiers such as silicone polyols,anionic emulsifiers, fatty acid soaps such as potassium stearate andfatty acid sulphates like sodium cetostearyl sulphate, ethoxylated fattyalcohols, sorbitan esters, ethoxylated sorbitan esters, ethoxylatedfatty acid esters such as ethoxylated stearates, ethoxylated mono, di-,and triglycerides, non-ionic self-emulsifying waxes, ethoxylated fattyacids, methylglucose esters such as polyglycerol-3 methyl glucosedistearate, and mixtures thereof. In particular embodiments, theemulsifier may be an ethoxylated fatty acid such as, for example, themixture of PEG-6/PEG-32/glycol stearate marketed under the trademarkTEFOSE™ 63 by Gattefosse. As used herein, TEFOSE™ 63 is considered anemulsifier and, in certain embodiments described herein, shall beconsidered a mixture of one or more polyethylene glycol (PEG) stearatesand one or more glycol stearates. In some embodiments, the emulsifiermay comprise a polyethylene glycol (PEG) stearate, a glycol stearate ora mixture thereof. In some embodiments, the cream may include from about1% to about 30% TEFOSE™ 63. In some embodiments, the cream may includefrom about 1% to about 20% TEFOSE™ 63. In other embodiments, the creammay include from about 1% to less than about 20% TEFOSE™ 63. Inembodiments, the cream may include from about 4% to about 12% TEFOSE™63. In some embodiments, the cream may include greater than about 8%TEFOSE™ 63. In other embodiments, the cream may include from about 8% toabout 10% TEFOSE™. In still other embodiments, the cream may includefrom about 8% to less than about 10% TEFOSE™ 63. In some embodiments,the cream may comprise TEFOSE™ 63 in an amount from about 1% to about20%. In various embodiments, the cream may comprise TEFOSE™ 63 in anamount from about 3% to about 15%, from about 5% to about 10%, fromabout 7% to about 10%, about 9% or about 8%. In certain embodiments,TEFOSE™ 63 is comprised of PEG-6 stearate, glycol stearate, and PEG-32stearate. In embodiments, the cream comprises PEG-6 stearate, glycolstearate, and PEG-32 stearate added as TEFOSE™ 63 in an about from about1% to about 20%, from about 3% to about 15%, from about 5% to about 10%,from about 7% to about 10%, about 9% or about 8%. In some embodiments,the cream comprises PEG-6 stearate, glycol stearate and PEG-32 stearate.In embodiments, the cream may comprise PEG-6 stearate, glycol stearateand PEG-32 stearate in a ratio of about 63:18.5:18.5, about75:12.5:12.5, about 50:25:25, about 75:15:10 or ranges of such ratios.In embodiments, the cream may comprise PEG-6 stearate, glycol stearateand PEG-32 stearate in a combined amount of from about 1% to about 30%,from about 1% to about 20%, from about 3% to about 15%, from about 5% toabout 10%, from about 7% to about 10%, about 9% or about 8%. Inembodiments, the cream may comprise PEG-6 stearate in an about fromabout 1% to about 20% by weight, from about 1% to about 10% by weight,from about 4% to about 10% by weight or from about 4% to about 6% byweight. In some embodiments, the cream may comprise glycol stearate inan amount from about 0.1% to about 10%, from about 0.1% to about 8%,from about 0.5% to about 5%, from about 0.5% to about 3%, from about0.5% to about 2%, or from about 0.8% to about 2%. In some embodiments,the cream may comprise PEG-32 stearate in an amount from about 0.1% toabout 10%, from about 0.1% to about 8%, from about 0.5% to about 5%,from about 0.5% to about 3%, from about 0.5% to about 2%, or from about0.8% to about 2%. In some embodiments, the cream may comprise PEG-6 maybe present in an amount of about 5% w/w; glycol stearate may be presentin an amount of about 1.5% w/w, PEG-32 stearate may be present in anamount of about 1.5% w/w.

In some embodiments, the hydrophilic-lipophilic balance (“HLB”) of theoil phase (or internal phase) of the cream may be very closely matchedwith the HLB values of the blend of emulsifiers in the cream. Forexample, the ingredients in the oil phase may include HLB values of:

Ingredient HLB value* Medium chain triglycerides 10.0 diisopropyladipate 9.0 oleyl alcohol 14.0 lanolin 12.0 *HLB values are approximateand may vary by about ±1 unit.Also, as example, the blend of emulsifiers may include HLB values of:

Ingredient HLB value* TEFOSE ™ 63  9.0-10.0 cetostearyl alcohol 15.5Macrogol (6) cetostearyl ether 10.0-12.0 Macrogol (25) cetostearyl ether15.0-17.0 *HLB values are approximate and may vary by about ±1 unit.

In some embodiments, the cream may comprise an emulsifier having ahydrophilic-lipophilic balance of from about 9.0 to about 17.0. In someembodiments, the hydrophilic-lipophilic balance is determined byGriffin's method. For example, in Trial 38, the HLB values for the oilphase and the emulsifier blend is as follows:

Oil Phase Component Desired HLB Percent in Formula Contribution Mediumchain 10.0 7.0 0.70 triglycerides Diisopropyl adipate 9.0 7.0 0.63 Oleylalcohol 14.0 7.0 0.98 Lanolin 12.0 2.0 0.24 Oil Phase SUM 2.55Emulsifier Blend Component HLB Value* Percent in Formula ContributionTefose 63  9 to 10 8.0 0.76 Cetostearyl alcohol 15.5 8.0 1.24 Macrogol(6) 10 to 12 2.0 0.22 cetostearyl ether Macrogol (25) 15 to 17 2.0 0.32cetostearyl ether Emulsifier Blend SUM 2.54 *For HLB value ranges, themid value was used to execute the calculation.

It may be understood from the above calculations that where percentagesof the oil phase ingredients are varied, physically stable emulsions maybe obtained by varying the percentages of blend emulsifiers so that therequired HLB of the oil phase remains closely matched. In embodiments,the HLB may be matched within +/−1 HLB value, within +/−0.5 HLB value orwithin +/−0.1 HLB value.

Without wishing to be bound by theory, it is surprising that, forexample, in Trial 38, using four neutral to hydrophilic emulsifiers,such as TEFOSE 63™ (having an HLB value from about 9.0 to about 10.0) orMacrogol (25) cetostearyl ether (having an HLB value from about 15.0 toabout 17.0), in the concentrations or proportions described, results ina cosmetically acceptable emulsion that is non-irritating. Non-ionicsurfactants such as those used in embodiments herein may containirritants such as polyethylene glycol (PEG). Such PEGylated or PEGcontaining surfactants may be irritating and may cause contactdermatitis at high levels. In some embodiments, the cream formulationmay comprise an emulsifier having an HLB value of from about 9.0 toabout 17.0 in cream embodiments described herein wherein the creamformulation is cosmetically acceptable and non-irritating. Inembodiments, the cream formulation may be non-irritating to evenpatients with extremely reactive and/or sensitive skin, such as, but notlimited to, that typically seen in patients with rosacea, eczema,dermatitis, and other conditions of the skin characterized by adisturbance of the epidermal barrier.

Furthermore, it is surprising that in some embodiments, the cream mayfurther produce a long lasting soothing effect on the skin. The term“soothing”, as used herein, means that the formulation is moisturizing,softening, cosmetically appealing, non-irritating or generally calmingand comforting to the skin or may decrease any erythema (or redness), ifpresent.

Thus, in some embodiments, the cream formulation is soothing to theskin. In some embodiments, the soothing effect of the cream formulationsof embodiments herein may be long-lasting. In some embodiments, thesoothing effect may last up to at least about four hours, at least aboutfive hours, at least about six hours, at least about seven hours, atleast about eight hours, at least about ten hours, at least about 12hours, at least about 15 hours, at least about 18 hours, at least about21 hours, at least about 24 hours or at least about 48 hours with asingle application. In some embodiments, the soothing effect may lastfor from about 1 to about 48 hours; from about 1 to about 24 hours; fromabout 1 to about 21 hours; from about 1 to about 18 hours; from about 1to about 16 hours; from about 1 to about 12 hours; from about 1 to about10 hours; from about 1 to about 8 hours; from about 2 to about 24 hours;from about 2 to about 16 hours; from about 2 to about 12 hours; fromabout 2 to about 8 hours; from about 4 to about 24 hours; from about 4to about 16 hours; from about 4 to about 12 hours; from about 4 to about8 hours; from about 6 to about 24 hours; from about 6 to about 16 hours;from about 6 to about 12 hours; from about 6 to about 8 hours; fromabout 2 to about 6 hours; from about 4 to about 6 hours, or combinationsthereof. In some embodiments, this soothing effect may be maintainedwith daily application of the cream formulation to the skin. In someembodiments, this soothing effect may be maintained for as long as thecream formulation is applied to the skin daily. In some embodiments,this soothing effect may be maintained with daily application of thecream formulation for at least about 1 month, at least about 2 months,at least about 3 months, at least about 4 months, at least about 5months, at least about 6 months, at least about 9 months, or at leastabout 12 months.

In some embodiments, it was surprisingly found that the creamformulation may produce long lasting effects on the skin and may modifythe long-term course of rosacea, i.e. it may be “disease modifying.”Specifically, in certain embodiments, the clinical effect of thecomposition may be maintained long after the final administration ofoxymetazoline composition of embodiments herein, including, withoutlimitation, improvement in erythema, telangiectasias, acute and chronicinflammatory lesions such as papules and pustules, phymas or acombination thereof. In some embodiments, the administration ofoxymetazoline composition of embodiments herein may slow progression ofthe disease or disorder, including, without limitation, rosacea,erythema, telangiectasias, acute and chronic inflammatory lesions suchas papules and pustules, phymas or a combination thereof.

Furthermore, in some embodiments, the therapeutic effect of creamformulations described herein may be maintained for at least about 30days, for at least 25 days, for at least 20 days, for at least 15 days,for at least 10 days after stopping the administration of the creamformulation. In some embodiments, the therapeutic effect may bemaintained for at least about 7 days, for at least about 5 days, or forat least about 4 days after stopping the administration of the creamformulation.

In some embodiments described herein, the cream formulation iscosmetically elegant and highly stable. Without wishing to be bound bytheory, it is believed that such cosmetically elegant and stableemulsions may restore and reinforce the epidermal barrier functionordinarily provided by healthy stratum corneum, ceramides, cholesteroland epidermal lipids, providing protection and restoring hydration tothe skin.

In some embodiments, the cream formulation comprises an emulsifier in anamount of greater than about 5% and is non-irritating. In someembodiments, the cream formulation comprises an emulsifier in an amountof greater than about 10% and is non-irritating. In some embodiments,the cream formulation comprises an emulsifier in an amount of greaterthan about 15% and is non-irritating. In some embodiments, the creamformulation comprises an emulsifier in an amount of greater than about20% and is non-irritating. In some embodiments, the cream formulationcomprises an emulsifier in an amount of greater than about 25% and isnon-irritating. In some embodiments, the cream formulation comprises anemulsifier in an amount of greater than about 30% and is non-irritating.In some embodiments, the cream formulation comprises propylene glycoland is non-irritating. In some embodiments, the cream formulationcomprises propylene glycol in an amount of greater than about 4% and isnon-irritating.

The creams of various embodiments may include any number of additionalcomponents such as, for example, preservatives, emulsion stabilizers, pHadjusters, chelating agents, viscosity modifiers, antioxidants,surfactants, emollients, opacifying agents, skin conditioners, buffers,fragrances and combinations thereof. In some embodiments, suchadditional components may provide a dual purpose. For example, certainsurfactants may also act as emulsifiers, certain emollients may also actas opacifying agents, and certain buffering agents may also act aschelating agents.

In another embodiment of the invention, the formulation may furthercomprise a topically active pharmaceutical or cosmetic agent destined,in part, to have a synergistic effect or a therapeutic effect associatedwith another skin complaint, condition or affliction. Examples of theseagents include: anti-rosacea agents such as metronidazole, precipitatedsulfur, sodium sulfacetamide, or azelaic acid; antibacterial agents(antibiotics) such as clindamycin phosphate, erythromycin, orantibiotics from the tetracycline family; antimycobacterial agents suchas dapsone; other antiacne agents such as retinoids, or benzoylperoxide; antiparasitic agents such as metronidazole, permethrin,crotamiton, thiabendazole, ivermectin or pyrethroids; antifungal agentssuch as compounds of the imidazole family such as miconazole,clotrimazole, econazole, ketoconazole, or salts thereof, polyenecompounds such as amphotericin B, compounds of the allylamine familysuch as terbinafine; steroidal anti-inflammatory agents such ashydrocortisone triamcinolone, fluocinonide, betamethasone valerate orclobetasol propionate, or non-steroidal anti-inflammatory agents such asibuprofen and salts thereof, naproxen and salts thereof, oracetaminophen; anesthetic agents such as the “amide” and “ester”anesthetics, including, but not limited to, lidocaine, prilocalne,tetracaine, hydrochloride and derivatives thereof; antipruriginousagents such as thenaldine, trimeprazine, or pramoxine; antiviral agentssuch as acyclovir; keratolytic agents such as alpha- and beta-hydroxyacids such as glycolic acid or salicylic acid, or urea; anti-freeradical agents (antioxidants) such as Vitamin E (alpha tocopherol) andits derivatives, Vitamin C (ascorbic acid), Vitamin A (retinol) and itsderivatives, and superoxide dismutases; antiseborrheic agents such aszinc pyrithione and selenium sulfide; antihistamines such ascyproheptadine or hydroxyzine; tricyclic antidepressants such as doxepinhydrochloride; antipsoriatic agents such as calcipotriene, anthralines,coal tar; immune modulating agents such as imiquimod, or the calcineurininhibitors pimecrolimus and tacrolimus, and chemotherapeutic agents suchas 5-fluorouracil, nitrogen mustard, carmustine, bexarotene,mitomycin-c. The topically active pharmaceutical or cosmetic agent mayinclude, without limitation, one or more of hydroxyacids, polyhydroxyacids, polyhydroxy lactones, ketoacids and related compounds; phenylalpha acyloxyalkanoic acids and derivatives; N-acyl-aldosamines,N-acylamino acids and related N-acyl compounds;N-(phosphonoalkyl)-aminocarbohydrates, N-(phosphonoalkyl)-amino acidsand their related N-(phosphonoalkyl)-compounds; local analgesics andanesthetics; anti-acne agents; anti-bacterial agents; anti-yeast agents;anti-fungal agents; anti-viral agents; anti-infective agents;anti-dandruff agents; anti-dermatitis agents; anti-eczema agents;anti-histamine agents; anti-pruritic agents; anti-emetics; anti-motionsickness agents; anti-inflammatory agents; anti-hyperkeratotic agents;antiperspirants; anti-psoriatic agents; anti-rosacea agents;anti-seborrheic agents; hair conditioners and hair treatment agents;anti-aging and anti-wrinkle agents; anti-anxiety agents; anti-convulsantagents; anti-depressant agents; sunblock and sunscreen agents; skinlightening agents; depigmenting agents; astringents; cleansing agents;corn, callus and wart removing agents; skin plumping agents; skinvolumizing agents; skin firming agents; matrix metalloproteinase (MMP)inhibitors; topical cardiovascular agents; wound-healing agents; gumdisease or oral care agents; amino acids; peptides; dipeptides;tripeptides; glutathione and its derivatives; oligopeptides;polypeptides; carbohydrates; aminocarbohydrates; vitamins;corticosteroids; tanning agents; hormones, retinoids or combinationsthereof.

In some embodiments, the topically active pharmaceutical or cosmeticagent may include, without limitation, abacavir, acebutolol,acetaminophen, acetaminosalol, acetazolamide, acetohydroxamic acid,acetylsalicylic acid, N-acylglutathione ethyl ester and other esters,N-acyl proline ethyl ester and other esters, acitretin, aclovate,acrivastine, actiq, acyclovir, adalimumab, adapalene, adefovirdipivoxil, adenosine, albuterol, alefacept, alfuzosin, allopurinol,alloxanthine, almotriptan, alprazolam, alprenolol, aluminum acetate,aluminum chloride, aluminum chlorohydroxide, aluminum hydroxide,amantadine, amiloride, aminacrine, p-aminobenzoic acid, aminocaproicacid, aminolevulinic acid, aminosalicylic acid, amiodarone,amitriptyline, amlodipine, amocarzine, amodiaquin, amorolfine,amoxapine, amphetamine, ampicillin, anagrelide, anastrozole, anthralin,apomorphine, aprepitant, arbutin, aripiprazole, ascorbic acid, ascorbylpalmitate, atazanavir, atenolol, atomoxetine, atropine, azathioprine,azelaic acid, azelastine, azithromycin, bacitracin, beclomethasonedipropionate, bemegride, benazepril, benzilic acid, bendroflumethiazide,benzocaine, benzonatate, benzophenone, benzoyl peroxide, benztropine,bepridil, betamethasone dipropionate, betamethasone valerate, botulinumtoxin, brimonidine, brompheniramine, bupivacaine, buprenorphine,bupropion, burimamide, butenafine, butoconazole, cabergoline, caffeicacid, caffeine, calcipotriene, camphor, candesartan cilexetil,capsaicin, carbamazepine, carbamide peroxide, cefditoren pivoxil,cefepime, cefpodoxime proxetil, celecoxib, cetirizine, cevimeline,chitosan, chlordiazepoxide, chlorhexidine, chloroquine, chlorothiazide,chloroxylenol, chlorpheniramine, chlorpromazine, chlorpropamide,ciclopirox, cilostazol, cimetidine, cinacalcet, ciprofloxacin,citalopram, citric acid, cladribine, clarithromycin, clemastine,clindamycin, clioquinol, clobetasol propionate, clocortolone pivalate,clomiphene, clonidine, clopidogrel, clotrimazole, clozapine, cocaine,codeine, cromolyn, crotamiton, cyclizine, cyclobenzaprine, cycloserine,cytarabine, dacarbazine, dalfopristin, dapsone, daptomycin,daunorubicin, deferoxamine, dehydroepiandrosterone, delavirdine,desipramine, desloratadine, desmopressin, desoximetasone, dexamethasone,dexmedetomidine, dexmethylphenidate, dexrazoxane, dextroamphetamine,diazepam, diclofenac, dicyclomine, didanosine, dihydrocodeine,dihydromorphine, diltiazem, 6,8-dimercaptooctanoic acid (dihydrolipoicacid), diphenhydramine, diphenoxylate, dipyridamole, disopyramide,dobutamine, dofetilide, dolasetron, donepezil, dopa esters, dopamide,dopamine, dorzolamide, doxepin, doxorubicin, doxycycline, doxylamine,doxypin, duloxetine, dyclonine, econazole, efalizumab, eflornithine,eletriptan, emtricitabine, enalapril, ephedrine, epinephrine, epinine,epirubicin, eptifibatide, ergotamine, erythromycin, escitalopram,esmolol, esomeprazole, estazolam, estradiol, etanercept, ethacrynicacid, ethinyl estradiol, ethyl pyruvate, etidocaine, etomidate,famciclovir, famotidine, felodipine, fentanyl, ferulic acid,fexofenadine, finasteride, flecamide, fluconazole, flucytosine,fluocinolone acetonide, fluocinonide, 5-fluorouracil, fluoxetine,fluphenazine, flurazepam, fluticasone propionate, fluvoxamine,formoterol, furosemide, galactarolactone, galactonic acid,galactonolactone, galantamine, gatifloxacin, gefitinib, gemcitabine,gemifloxacin, glucarolactone, gluconic acid, gluconolactone, glucuronicacid, glucuronolactone, glycolic acid, griseofulvin, guaifenesin,guanethidine, N-guanylhistamine, haloperidol, haloprogin,hexylresorcinol, homatropine, homosalate, hydralazine,hydrochlorothiazide, hydrocortisone, hydrocortisone 21-acetate,hydrocortisone 17-butyrate, hydrocortisone 17-valerate, hydrogenperoxide, hydromorphone, hydroquinone, hydroquinone monoether,hydroxyzine, hyoscyamine, hypoxanthine, ibuprofen, ichthammol,idarubicin, imatinib, imipramine, imiquimod, indinavir, indomethacin,infliximab, irbesartan, irinotecan, isoetharine, isoproterenol,itraconazole, kanamycin, ketamine, ketanserin, ketoconazole, ketoprofen,ketotifen, kojic acid, labetalol, lactic acid, lactobionic acid,lamivudine, lamotrigine, lansoprazole, letrozole, leuprolide,levalbuterol, levofloxacin, lidocaine, linezolid, lobeline, loratadine,loperamide, losartan, loxapine, lysergic diethylamide, mafenide, malicacid, maltobionic acid, mandelic acid, maprotiline, mebendazole,mecamylamine, meclizine, meclocycline, memantine, menthol, meperidine,mepivacaine, mequinol, mercaptopurine, mescaline, metanephrine,metaproterenol, metaraminol, metformin, methadone, methamphetamine,methotrexate, methoxamine, methyldopa esters, methyldopamide,3,4-methylenedioxymethamphetamine, methyllactic acid, methyl nicotinate,methylphenidate, methyl salicylate, metiamide, metolazone, metoprolol,metronidazole, mexiletine, miconazole, midazolam, midodrine, miglustat,minocycline, minoxidil, mirtazapine, mitoxantrone, moexiprilat,molindone, monobenzone, morphine, moxifloxacin, moxonidine, mupirocin,nadolol, naftifine, nalbuphine, nalmefene, naloxone, naproxen,nefazodone, nelfinavir, neomycin, nevirapine, nicardipine, nicotine,nifedipine, nimodipine, nisoldipine, nitrofurantoin, nizatidine,norepinephrine, nystatin, octopamine, octreotide, octylmethoxycinnamate, octyl salicylate, ofloxacin, olanzapine, olmesartanmedoxomil, olopatadine, omeprazole, ondansetron, oxiconazole,oxotremorine, oxybenzone, oxybutynin, oxycodone, oxymetazoline, padimate0, palonosetron, pantothenic acid, pantoyl lactone, paroxetine,pemoline, penciclovir, penicillamine, penicillins, pentazocine,pentobarbital, pentostatin, pentoxifylline, pergolide, perindopril,permethrin, phencyclidine, phenelzine, pheniramine, phenmetrazine,phenobarbital, phenol, phenoxybenzamine, phentolamine, phenylephrine,phenylpropanolamine, phenyloin, N-(phosphonomethyl)-glycine,N-(phosphonomethyl)-creatine, N-(phosphonomethyl)-tyramine,physostigmine, pilocarpine, pimecrolimus, pimozide, pindolol,pioglitazone, pipamazine, piperonyl butoxide, pirenzepine, podofilox,podophyllin, povidone iodine, pramipexole, pramoxine, prazosin,prednisone, prenalterol, prilocalne, procainamide, procaine,procarbazine, praline, promazine, promethazine, promethazine propionate,propafenone, propoxyphene, propranolol, propylthiouracil, protriptyline,pseudoephedrine, pyrethrin, pyrilamine, pyrimethamine, quetiapine,quinapril, quinethazone, quinidine, quinupristin, rabeprazole,reserpine, resorcinol, retinal, 13-cis retinoic acid, retinoic acid,retinol, retinyl acetate, retinyl palmitate, ribavirin, ribonic acid,ribonolactone, rifampin, rifapentine, rifaximin, riluzole, rimantadine,risedronic acid, risperidone, ritodrine, rivastigmine, rizatriptan,ropinirole, ropivacaine, salicylamide, salicylic acid, salmeterol,scopolamine, selegiline, selenium sulfide, serotonin, sertaconazole,sertindole, sertraline, shale tar, sibutramine, sildenafil, sotalol,streptomycin, strychnine, sulconazole, sulfacetamide, sulfabenz,sulfabenzamide, sulfabromomethazine, sulfacetamide (sodiumsulfacetamide), sulfachlorpyridazine, sulfacytine, sulfadiazine,sulfadimethoxine, sulfadoxine, sulfaguanole, sulfalene, sulfamethizole,sulfamethoxazole, sulfanilamide, sulfapyrazine, sulfapyridine,sulfasalazine, sulfasomizole, sulfathiazole, sulfisoxazole, sulfur,tacrolimus, tadalafil, tamsulosin, tartaric acid, tazarotene, tegaserol,telithromycin, telmisartan, temozolomide, tenofovir disoproxil,terazosin, terbinafine, terbutaline, terconazole, terfenadine,tetracaine, tetracycline, tetrahydrozoline, thalidomide, theobromine,theophylline, thiabendazole, thioctic acid (lipoic acid), thioridazine,thiothixene, thymol, tiagabine, timolol, timidazole, tioconazole,tirofiban, tizanidine, tobramycin, tocamide, tolazoline, tolbutamide,tolnaftate, tolterodine, tramadol, tranylcypromine, trazodone,triamcinolone acetonide, triamcinolone diacetate, triamcinolonehexacetonide, triamterene, triazolam, triclosan, triflupromazine,trimethoprim, trimipramine, tripelennamine, triprolidine, tromethamine,tropic acid, tyramine, undecylenic acid, urea, urocanic acid, ursodiol,vardenafil, venlafaxine, verapamil, vitamin E acetate, voriconazole,warfarin, wood tar, xanthine, zafirlukast, zaleplon, zinc pyrithione,ziprasidone, zolmitriptan, zolpidem or combinations thereof.

Embodiments are not limited by the number or type of preservatives usedin the creams described herein. For example, preservatives useful inembodiments may include, but are not limited to, pentylene glycol,ethylene diamine tetra acetate (EDTA) and its salts, chlorhexidine andits diacetate, dihydrochloride, digluconate derivatives,1,1,1-trichloro-2-methyl-2-propanol, parachlorometaxylenol,polyhexamethylenebiguanide hydrochloride, dehydroacetic acid,diazolidinyl urea, 2,4-dichlorobenzyl alcohol,4,4-dimethyl-1,3-oxazolidine, formaldehyde, glutaraldehyde,dimethylidantoin, imidazolidinyl urea,5-chloro-2-methyl-4-isothiazolin-3-one, ortho-phenylphenol, benzylalcohol, benzoic acid and its salts, 4-hydroxybenzoic acid and itsmethyl-, ethyl-, propyl-, isopropyl-, butyl-, isobutyl-esters(parabens), methylparaben, propylparaben, isopropylparabens,isobutylparabens, butylparabens, ethylparaben, trichlosan,2-phenoxyethanol, phenyl mercuric acetate, quaternium-15,methylsalicylate, salicylic acid and its salts, sorbic acid and itssalts, iodopropanyl butylcarbamate, calcium sorbate, zinc pyrithione,5-bromo-Snitro-1,3-dioxane, 2-bromo-2-nitropropane-1,3-diol, sulfites,bisulfites, and benzalkonium chloride, phenoxyethanol, 2-phenoxyethanol,chloroxylenol, diazolidinyl urea, and combinations thereof. Inembodiments, the cream may include any preservative, including, but notlimited to those listed above or a combination thereof. In certainembodiments, the cream may include a combination of methylparaben,propylparaben, and 2-phenoxyethanol.

Preservatives may be provided in any concentration known in the art. Forexample in some embodiments, the cream may include from about 0.01% toabout 3% by weight of any one preservative, and in other embodiments,the cream may include from about 0.05% to about 1.2% by weight of anyone preservative. Thus, in creams that include more than onepreservative each preservative may be provided at about 0.01% to about3% by weight or from about 0.05% to about 1.2% by weight.

The creams of various embodiments may include any chelating agent orcombination of chelating agents. Examples of the chelating agents usefulin various embodiments include, but are not limited to, alanine, sodiumpolyphosphate, sodium methaphosphate, citric acid, phosphoric acid,tartaric acid, ethylenediamine tetra acetic acid (Edetate, EDTA) andderivatives and salts thereof, dihydroxyethyl glycine, and mixturesthereof. In particular embodiments, the chelating agent may be EDTA oredetate disodium, dihydrate.

The chelating agents may be provided in any effective amount. Forexample, in some embodiments, the cream may include from about 0.001% toabout 2% by weight chelating agent, and in other embodiments, the creammay include from about 0.05% to about 1% by weight chelating agent.

In some embodiments, the cream may include one or more viscositymodifiers. The viscosity modifier of such embodiments may generallyinclude a high molecular weight compound such as, for example,carboxyvinyl polymer, carboxymethyl cellulose, polyvinyl pyrrolidone,hydroxyethyl cellulose, methyl cellulose, natural gum such as gelatinand tragacanth gum, and various alcohols such as polyvinyl alcohol. Inother embodiments, the viscosity modifier may include ethanol orisopropyl alcohol. In some embodiments, the viscosity modifier may be ahigh molecular weight saturated and unsaturated fatty alcohol such as,but are not limited to, carbitol, lauryl alcohol, myristyl alcohol,cetyl alcohol, isocetyl alcohol, stearyl alcohol, isostearyl alcohol,hydroxystearyl alcohol, oleyl alcohol, ricinoleyl alcohol, behenylalcohol, erucyl alcohol, 2-octyldodecanyl alcohol, cetearyl alcohol,lanolin alcohol, and the like, and in certain embodiments, the viscositymodifier may be oleyl alcohol.

The viscosity modifier may be provided in any amount necessary to createa cream that fits within the viscosity described above, and in certainembodiments, the cream may include from about 0.1% to about 30% byweight viscosity modifier. In some embodiments, the cream may includefrom about 0.5% to about 20% by weight viscosity modifier. In someembodiments, the cream may include from about 0.5% to about 10% byweight viscosity modifier. In some embodiments, the cream may include aviscosity modifier in an amount from about 2% to about 10% by weight.

The cream of certain embodiments may include one or more antioxidants.Numerous antioxidants are known in the art, and any such antioxidant maybe used to prepare the oxymetazoline creams described herein. Examplesof suitable antioxidants include, but are not limited to, amino acidssuch as glycine, histidine, tyrosine, trytophan and derivatives thereof,imidazoles such as urocanic acid and derivatives thereof, peptides, suchas D,L-carnosine, D-carnosine, L-carnosine and derivatives thereof suchas anserine, carotinoids, carotenes such as α-carotone, β-carotene,lycopene, and derivatives thereof, chlorogenic acid and derivativesthereof, lipoic acid and derivatives thereof such as dihydrlipoic acid,aurothioglycose, propylthiouracil and other thiols such as thioredoxin,glutathione, cysteine, cystine, cystamine and glycosyl, N-acetyl,methyl, ethyl, propyl, amyl, butyl, lauryl, palmitoyl, oleyl,α-linoleyl, cholesteryl and glyceryl esters and salts thereof, dilaurylthiodipropionate, distearyl thiodipropionate, thiodipropionic acid andderivatives thereof such as esters, ethers, peptides, lipids,nucleotides, nucleosides, and salts, sulfoximine compounds such asbuthionine sulfoximines, homocysteine sulfoximine, buthionine sulfones,penta-, hexa-, hepta-thionine sulfoximine, unsaturated fatty acids andderivatives thereof such as α-linolenic acid, linoleic acid, oleic acid,folic acid and derivatives thereof, ubiquinone and ubiquinol andderivatives thereof, vitamin C and derivatives there of such as ascorbylpalmitate, magnesium ascorbyl phosphate, ascorbyl acetate, tocopheralsand derivatives such as vitamin E acetate, vitamin A and derivativessuch as vitamin A palmitate, vitamin B and derivatives thereof,coniferyl benzoate of benzoin resin, rutinic acid and derivativesthereof, α-glycosylrutin, ferulic acid, furfurylidene glucitol,carnosine, butyl hydroxytoluene, trihydroxy-butyrophenone, uric acid andderivatives thereof, mannose and derivatives thereof, superoxidedismutase, zinc and derivatives thereof such as ZnO, ZnSO₄, selenium andderivatives thereof such as selenium methionine, stilbene andderivatives thereof such as stilbene oxide, trans-stilbene oxide and thelike. In particular exemplary embodiments, the one or more antioxidantsmay include vitamin B, nordihydroguaiaretic acid, butylatedhydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate,erythorbate acid, sodium erythorbate, ascorbir palmitate, and ascorbirstearate. butyl hydroxyanisole, and gallic esters, and in someembodiments, the one or more antioxidants may include BHT.

The one or more antioxidants may be provided in any suitable amount. Forexample in some embodiments, one or more antioxidants may be from about0.001% to about 3% by weight of the cream, and in other embodiments, theone or more antioxidants may be from about 0.01% to about 1% by weightof the cream or from about 0.01% to about 0.50% by weight of the cream.

In some embodiments, oxymetazoline creams described herein may includeone or more surfactants. Such embodiments are not limited by type ofsurfactant used; for example, in some embodiments, the one or moresurfactants may be anionic surfactants such as alkyl sulfates,alkylether sulfates, alkylsulfonates, alkylaryl sulfonates, alkylsuccinates, alkyl sulfosuccinates, N-alkoylsarcosinates, acyl taurates,acyl isethionates, alkyl phosphates, alkyl ether phosphates, alkyl ethercarboxylates, α-olefinsulfonates, and the alkali metal and alkalineearth metal salts and ammonium and triethanolamine salts thereof. Suchalkyl ether sulfates, alkyl ether phosphates and alkyl ethercarboxylates can have between 1 and 10 ethylene oxide or propylene oxideunits, and in some embodiments, 1 to 3 ethylene oxide units, permolecule. More specific examples include, but are not limited to, sodiumlauryl sulfate, ammonium lauryl sulfate, sodium lauryl ether sulfate,ammonium lauryl ether sulfate, sodium lauryl sarcosinate, sodium oleylsuccinate, ammonium lauryl sulfosuccinate, sodium dodecylbenzenesulfonate, triethanolamine dodecylbenzenesulfonate. In otherembodiments, the one or more surfactants may be amphoteric surfactantssuch as, for example, alkylbetaines, alkylamidopropylbetaines,alkylsulfobetaines, alkylglycinates, alkylcarboxyglycinates,alkylamphoacetates or α-propionates, alkylamphodiacetates orα-dipropionates, and more specifically, cocodimethylsulfopropylbetaine,lauryl betaine, cocamidopropylbetaine or sodium cocamphopropionate.

In certain embodiments, the one or more surfactants may be non-ionicsurfactants such as, for example, the reaction products of aliphaticalcohols or alkylphenols having 6 to 20 carbon atoms in a linear orbranched alkyl chain with ethylene oxide and/or propylene oxide wherethe alkylene oxide may be from about 6 moles to about 60 moles per moleof alcohol. In particular embodiments, non-ionic surfactants may includealkylamine oxides, mono- and dialkylalkanolamides, fatty acid esters ofpolyethylenenglycols, ethoxylated fatty acids amides, saturated fattyacid alcohols reacted with ethylene oxide, alkyl polyglycosides, andsorbitan ether esters, and in some embodiments, the non-ionic surfactantmay be ceteareth-2, ceteareth-3, ceteareth-4, ceteareth-5, ceteareth-6,ceteareth-7, ceteareth-8, ceteareth-9, ceteareth-10, ceteareth-11,ceteareth-12, ceteareth-13, ceteareth-14, ceteareth-15, ceteareth-16,ceteareth-17, ceteareth-18, ceteareth-20, ceteareth-22, ceteareth-23,ceteareth-24, ceteareth-25, ceteareth-27, ceteareth-28, ceteareth-29,ceteareth-30, ceteareth-33, ceteareth-34, ceteareth-40, ceteareth-50,ceteareth-55, ceteareth-60, ceteareth-80, ceteareth-100, and the like orcombinations thereof, or one or more ceteareth in combination with afatty acid alcohol such as stearyl alcohol, oleyl alcohol, linoleylalcohol, arachidyl alcohol, cetyl alcohol, and the like. In certainembodiments, the one or more surfactants may be a commercially availableceteareth containing surfactants such as CREMOPHOR EL®, CREMOPHOR A-6®,CREMPHOR A-25® or combinations thereof.

The one or more surfactants of various embodiments may make up fromabout 0.1% to about 50% by weight of the cream and in some embodiments,from about 0.5% to about 20% by weight of the cream. In embodiments inwhich more than one surfactant is provided in the oxymetazoline cream,each surfactant may be from about 0.5% to about 12% by weight of thecream, and in some embodiments, each surfactant of the oxymetazolinecream containing two or more surfactants may be from about 0.5% to about5% by weight of the cream.

In some embodiments, the oxymetazoline cream may include one or moreemollients. Generally, emollients function enable the cream and byextension the active agent to remain on the skin surface or in thestratum corneum. Emollients are well known in the art and are listed,for example, the International Cosmetic Ingredient Dictionary, EighthEdition, 2000, which is hereby incorporated by reference in itsentirety. In certain embodiments, the one or more emollient may be fattyesters, fatty alcohols, or combinations thereof including, but notlimited to, diisopropyl adipate, oleyl alcohol, lanolin, isopropylmyristate, isopropyl palmitate, caprylic/capric triglycerides, cetyllactate, cetyl palmitate, hydrogenated castor oil, glyceryl esters,hydroxycetyl isostearate, hydroxy cetyl phosphate, isopropylisostearate, isostearyl isostearate, diisopropyl sebacate,polyoxypropylene (5) poloxyethylene (20) cetyl ether (PPG-5-Ceteth-20),2-ethylhexyl isononoate, 2-ethylhexyl stearate, C₁₂ to C₁₆ fattyalcohol, C₁₂ to C₁₆ fatty alcohol lactate, isopropyl lanolate,2-ethyl-hexyl salicylate, and mixtures thereof. In some embodiments, theone or more emollients may be a combination of fatty alcohols. Incertain embodiments, the one or more emollients may be 1-hexadecanol,acetylated lanolin, behenocyl dimethicone, C12-15 alkyl benzoate,cetearyl octanoate, cocoglycerides, dicaprylate/dicaprate dimethiconecopolyol, dimethiconol, dioctyl adipate, glyceryl stearate, isocetylalcohol, isohexadecane, isopentylcyclohexanone, isopropyl palmitate,lauryl lactate, mineral oil, methoxy peg-22/dodecyl glycol copolymer,myristyl lactate, ocryldodecyl neopentanoate, octyl cocoate, octylpalmitate, octyl stearate, octyldodecyl neopentanoate, polyglyceryl-4isosterate, polyoxyl 40 stearate, polyoxymethylene urea, potassiumsorbate, propylene glycol, propylene glycol isoceth-3 acetate, andpropylene glycol myristyl ether acetate.

The emollient may be provided in any suitable amount. For example, insome embodiments, the one or more emollient may be from about 1% toabout 50% by weight of the cream, and in other embodiments, theemollient may be from about 2% to about 7% by weight of theoxymetazoline cream. As indicated above, the emollient may also beprovided in an amount sufficient to provide a ratio of emulsifier toemollient of from about 0.002:1 to about 50:1. In some embodiments, theratio of emulsifier to emollient is from about 0.1:1 to about 1.8:1,from about 0.2:1 to about 1.8:1, from about 0.3:1 to about 1.8:1, fromabout 0.4:1 to about 1.8:1, from about 0.5:1 to about 1.8:1, from about0.7:1 to about 1.8:1, about 0.3:1 to about 1.5:1, about 0.3:1 to about1.285:1, about 0.3 to about 1:1, about 0.4:1 to about 1.5:1, about 0.4:1to about 1.285:1, about 0.4:1 to about 1:1, about 0.7:1 to about 1.8:1,about 0.7:1 to about 1.5:1, about 0.7:1 to about 1.285:1, about 0.7:1 toabout 1:1, about 0.73:1 to about 1.8:1, about 0.73:1 to about 1.5:1,about 0.73:1 to about 1.285:1, about 0.73:1 to about 1:1, about 0.87:1to about 1.5:1, about 0.87:1 to about 1.285:1, about 0.87:1 to about1:1, about 1:1 to about 1.285:1, about 1:1 to about 1.25:1, about 1:1 toabout 1.2:1, about 1:1, about 0.87:1, about 0.73:1, or about 0.7:1, orcombinations thereof. In such embodiments, the percentage by weight ofemollient in the cream will fall within these ranges. In someembodiments, the emulsifier may comprise TEFOSE™ 63, cetostearyl alcoholmacrogol (6) cetostearyl ether, macrogol(25) cetostearyl ether orcombinations thereof. In some embodiments, the cream may comprise anemulsifier of low molecular weight polyethylene glycol(s) or its esters(e.g. PEG-32 stearate, PEG-6 stearate). In some embodiments, the ratioof TEFOSE™ 63 to cetostearyl alcohol is from about 0.7:1 to about 1.8:1,about 0.7:1 to about 1.5:1, about 0.7:1 to about 1.285:1, about 0.7 toabout 1:1, about 0.73:1 to about 1.8:1, about 0.73:1 to about 1.5:1,about 0.73:1 to about 1.285:1, about 0.73:1 to about 1:1, about 0.87:1to about 1.5:1, about 0.87:1 to about 1.285:1, about 0.87:1 to about1:1, about 1:1 to about 1.285:1, about 1:1 to about 1.25:1, about 1:1 toabout 1.2:1, about 1:1, about 0.87:1, about 0.73:1, or about 0.7:1 orcombinations thereof. In some embodiments, the emollient may comprisetriglycerides medium chain, diisopropyl adipate, oleyl alcohol, lanolinor combinations thereof.

Without wishing to be bound by theory, from the standpoint of emulsionstability, if an ester is not properly emulsified, the emulsion willexhibit “creaming”: separation of the non-polar phase to the top of thecream and aqueous layer underneath. It is believed that the embodimentsdescribed herein contain no “true” oil phase and the medium chaintriglycerides, diisopropyl adipate and oleyl alcohol are not “true”oils, thus forming an oil-phase-less emulsion. This may make the creamformulation of embodiments herein extremely difficult to emulsify and itmay explain why there are so many varied emulsifiers.

In certain embodiments, the oxymetazoline cream may include one or moreopacifying agents. Opacifying agents provide color or whiteness to acomposition that may otherwise be clear of would have an undesirablecolor. In some embodiments, components such as, for example, emollients,surfactants, and/or emulsifiers may provide sufficient opaqueness. Inother embodiments, one or more additional opacifying agents may beprovided to the cream. Opacifying agents are well known in the art andinclude, but are not limited to, higher fatty alcohols such as cetyl,stearyl, cetostearyl alcohol, arachidyl and behenyl alcohols, solidesters such as cetyl palmitate, glyceryl laurate, stearamideMEA-stearate, high molecular weight fatty amides and alkanolamides andvarious fatty acid derivatives such as propylene glycol and polyethyleneglycol esters. In other embodiments, opacifying agents may includeinorganic materials such as, for example, magnesium aluminum silicate,zinc oxide, titanium dioxide or other sunblocking agents.

In embodiments in which an opacifying agent is used, the opacifyingagent may be provided in any amount necessary to provide the desiredopaqueness. In such embodiments, the opacifying agent may generally befrom about 0.01% to about 20% by weight of the cream, and in someembodiments, the opacifying agent may be from about 0.01% to about 5% orabout 0.02% to about 2% by weight of the cream.

In some embodiments, the oxymetazoline cream may include one or moreskin conditioners. Skin conditioners are components that may generallyimprove moisture retention in the skin, retard evaporation of water fromthe skin, and cause plasticization/softening of the skin. Common skinconditioners include, for example, mineral oil, petrolatum, aliphaticalcohols, lanolin and its derivatives, fatty acids, glycol fatty acids,sugars, glycerin, propylene glycol, sorbitols, and polyethylene glycols,vitamins and herbal derivatives. Additional skin conditioners can befound in CTFA Cosmetic Ingredient Handbook, 1st Ed., 1988, which ishereby incorporated herein by reference in its entirety. In someembodiments, the one or more skin conditioners may include, but are notlimited to, humectants, such as fructose, glucose, glycerin, propyleneglycol, glycereth-26, mannitol and urea, pyrrolidone carboxylic acid,hydrolyzed lecithin, coco-betaine, cysteine hydrochloride, glutamine,polyoxypropylene (15) polyoxyethylene (PPG-15), sodium gluconate,potassium aspartate, oleyl betaine, thiamine hydrochloride, sodiumlaureth sulfate, sodium hyaluronate, hydrolyzed proteins, hydrolyzedkeratin, amino acids, amine oxides, water-soluble derivatives ofvitamins A, E and D, amino-functional silicones, ethoxylated glycerin,α-hydroxy acids and salts thereof, water-soluble fatty oil derivatives,such as PEG-24 hydrogenated lanolin, almond oil, grape seed oil andcastor oil; numerous other water-soluble skin conditioners listed, andmixtures thereof. In certain embodiments, the skin conditioners mayinclude lanolin or lanolin derivatives, caprylic capric/triglyceride,diisopropyl adipate, and combinations thereof.

Skin conditioners may be provided to the creams of various embodimentsin any amount known in the art, and the amount of skin conditionerprovided may vary depending upon the type of skin condition orcombination of skin conditioners used. In general, the creams ofembodiments may include a conditioner in an amount from about 1% toabout 50% by weight of the cream or from about 1% to about 25% by weightof the cream.

The oxymetazoline creams of various embodiments may be of neutral tomildly acidic pH to allow for comfortable application to the subject'sskin, particularly in light of the disease state or condition sufferedby the subject. For example, in various embodiments, the pH of thecreams may be from about 2.5 to about 7.0, from about 4.0 to about 7.0,or from about 4.0 to about 5.5 at room temperature. In otherembodiments, the pH of such creams may be about 4.5 to about 5.5 at roomtemperature, and in particular embodiments, the pH of the creams may beabout 4.5 at room temperature. Any components or combination ofcomponents known and useful in the art may be used to achieve anappropriate pH such as, for example, pH regulators including, but notlimited to, lactic acid, citric acid, sodium citrate, glycolic acid,succinic acid, phosphoric acid, monosodium phosphate, disodiumphosphate, oxalic acid, dl-malic acid, calcium carbonate, sodiumhydroxide and sodium carbonate, sodium hydrogen carbonate, and ammoniumhydrogen carbonate. In various embodiments, the total buffer capacitymay be from about from about 0 mM to about 600 mM; from about 0 mM toabout 600 mM; from about 5 mM to about 600 mM; from about 5 mM to about400 mM; from about 5 mM to about 300 mM; from about 5 mM to about 200mM; from about 200 mM to about 400 mM; about 0 mM, about 100 mM, about200 mM, about 300 mM, about 400 mM, about 500 mM, or about 600 mM.

Embodiments of the invention also include methods for preparingpharmaceutical compositions as described above by, for example,conventional mixing and the like. For example, in some embodiments,oxymetazoline may be combined with any combination of componentsdescribed above in purified water using conventional mixing, and after astable emulsion has formed, the pH and viscosity may be adjusted usingknown methods to achieve a cream having an appropriate pH. In otherembodiments, various combinations of components may be combined inpurified water by conventional mixing and oxymetazoline may then beadded to the mixture. The pH, viscosity, opaqueness, and/or density maybe adjusted to achieve a cream which is cosmetically acceptable.

Embodiments are directed to methods of making the cream formulationcomprising making a first solution comprising the steps of dissolvingpreservatives, such as methylparaben and propylparaben, into a solvent,such as polyethylene glycol 300, mixing with a magnetic stirrer untilthe mixture becomes homogeneous, adding other preservatives, such as2-phenoxyethanol, to the mixture; making a second solution comprisingthe steps of heating purified water, and a chelating agent, such asdisodium edetate (EDTA); making an oil phase comprising addingemulsifiers, such as Tefose 63, cetostearyl alcohol, Cremophor A-6 andCremaphor A-25; antioxidants, such as butylated hydroxytoluene;emollients, such as lanolin, diisopropyl adipate, triglycerides mediumchain; and viscosity modifiers, such as cetostearyl alcohol; heating andmixing the oil phase; dissolving oxymetazoline into the second solutionto create an aqueous phase; adding the first solution to the aqueousphase to make an aqueous phase solution; and adding the aqueous phasesolution to the oil phase to make a cream.

Embodiments are directed to methods of making the cream formulationcomprising a “one-pot” process. In the one-pot process, the batch may bemanufactured in one vessel, kettle or container that can be heated bymeans of a steam or a heated fluid. First, an oil phase may be madecomprising adding emulsifiers, such as Tefose 63, cetostearyl alcohol,Cremophor A-6 and Cremaphor A-25; antioxidants, such as butylatedhydroxytoluene; emollients, such as lanolin, diisopropyl adipate,triglycerides medium chain; and viscosity modifiers such as cetostearylalcohol, heating and mixing the oil phase, then separately in a smallcontainer preparing a side-mix by dissolving preservatives, such asmethylparaben and propylparaben, into a solvent, such as polyethyleneglycol 300, mixing with a magnetic stirrer until the mixture becomeshomogeneous, adding other preservatives, such as 2-phenoxyethanol, tothe mixture; and a chelating agent, such as disodium edetate (EDTA) andadding this solution to the oil phase, mixing and heating this solutionto high temperature and then adding slowly the purified water, the wateris added at a rate that the temperature in the pot is maintained atabove about 70 degrees C.; once all the water has been added and thecream has been made, dissolving oxymetazoline into the cream.

Yet other embodiments are directed to methods for using thepharmaceutical compositions. In general, the oxymetazoline creamsdescribed herein may be administered topically to the skin, and in someembodiments, the oxymetazoline creams may be applied to portions of theskin that exhibit or may be prone to papules, pustules, otherinflammatory lesions, phymas (skin thickening) or erythema associatedwith rosacea, purpura, telangiectasias, keratosis pilaris, lupusmiliaris disseminatus faciei or the like. In other embodiments,oxymetazoline cream may be applied over an entire skin area includingthose areas not currently exhibiting or prone to papules, pustules,other inflammatory lesions, phymas (skin thickening) or erythemaassociated with rosacea, purpura, telangiectasias, keratosis pilaris,lupus miliaris disseminatus faciei or the like.

In various embodiments, the pharmaceutical compositions may be appliedto provide an effective amount of oxymetazoline to the subject, and incertain embodiments, the pharmaceutical compositions may be provided inan effective amount to a skin area exhibiting or prone to the symptomsof rosacea, telangiectasias, skin thickening, pustules, papules, otherskin erythemas, purpura, keratosis pilaris, lupus miliaris disseminatusfaciei or the like. In some embodiments, an effective amount may beapplied to the skin of the subject in need of treatment as the resultfrom a single application of the oxymetazoline cream. In otherembodiments, the oxymetazoline cream may be reapplied over the courseof, for example, a day, a week, a month, several months, or severalyears or until the condition is resolved. For example, in one exemplaryembodiment, a therapeutic method may include applying the oxymetazolinecreams described herein to a skin area exhibiting or prone to symptomsof rosacea, skin thickening, telangiectasias, pustules, papules, otherskin erythemas, purpura, keratosis pilaris, lupus miliaris disseminatusfaciei or the like once per day as long as the symptoms persist. Inother embodiments, the oxymetazoline cream may be applied as amaintenance therapy, wherein the cream is continuously applied as neededor applied on a scheduled basis over time while the subject is in needof such treatment. In embodiments, a therapeutic method may includeapplying the cream once per day, 2 times per day, 3 times per day, 4times per day or as needed or prescribed. In some embodiments, atherapeutic method may include applying the cream pro re nata (PRN or asneeded). In other embodiments, a therapeutic method may include applyingthe oxymetazoline cream 2 times per day, for example, every 4 hours, aslong as the symptoms persist. In other exemplary embodiments, atherapeutic method may include applying the oxymetazoline creams 2 ormore times, for example, every 6 hours or every 12 hours, per day aslong as the symptoms persist. In such embodiments, application of theoxymetazoline creams may be carried out until the symptoms of rosacea,skin thickening, telangiectasias, pustules, papules, other skinerythemas, purpura, keratosis pilaris, lupus miliaris disseminatusfaciei or the like have been substantially reduced or eliminated, and insome embodiments, the amount of oxymetazoline cream applied or thefrequency of application may be modified throughout the course oftreatment based on the subject's reaction to the pharmaceuticalcomposition and the clinician's recommendations. For example, aftersymptom reduction or elimination is observed, the amount ofoxymetazoline cream applied or the frequency of applications may bemodified to maintain a therapeutic effect.

The creams of various embodiments may be applied by any method. Forexample, in some embodiments, the oxymetazoline cream may be applied byhand by the subject or another person, such as a clinician. In otherembodiments, the oxymetazoline cream may be packaged with an applicatorsuch as a wand, swath of cloth, or applicator pad, and in still otherembodiments, measured doses of the oxymetazoline cream may be packagedfor application by hand. Without wishing to be bound by theory,providing the oxymetazoline cream with a prepackaged applicator or inmeasured doses may provide a more controlled dose. In general, thesubject and/or clinician will ensure that the oxymetazoline cream isapplied evenly over the skin area to be treated.

EXAMPLES

Although the present invention has been described in considerable detailwith reference to certain preferred embodiments thereof, other versionsare possible. Therefore, the spirit and scope of the appended claimsshould not be limited to the description and the preferred versionscontained within this specification. Various aspects of the presentinvention will be illustrated with reference to the followingnon-limiting examples.

Example 1

The amount per batch (kg) for each component of the oxymetazoline creamprepared as described below are provided with their concentration byweight of the total cream in Table 1. Table 2 illustrates a function andamount per batch (kg) for each component of the cream prepared asdescribed below with each component's concentration by weight of thetotal cream wherein Tefose™ 63 is replaced by a mixture of PEG-6Stearate, Glycol Stearate and PEG-32 Stearate.

Solution 1: In a 2 L glass beaker, 44.0 g of methylparaben, NF and 11.0g of propylparaben, NF was dissolved into 880 g of polyethylene glycolby mixing with a magnetic stirrer until the mixture became homogeneous.Once the parabens were dissolved, 176.0 g of phenoxyethanol Ph Eur wasadded to the mixture.

Solution 2: In a separate 36 L capacity stainless steel beaker, heatpurified 11305 g of purified water was heated to 75° C. to 78° C. usinga hot plate, and 2.2 g of disodium edetate (EDTA), USP, 44.0 g ofanhydrous citric acid, USP, and 66.0 g of sodium citrate dehydrate, USPwas added to the heated water using a low mixing speed (450 rpm) whilemaintaining the temperature of the solution at 75° C. to 78° C.

Oil Phase: Into a reactor vessel, preferably an anchor-type,propeller-equipped reactor vessel, 11.0 g of butylated hydroxytoluene,NF, 1760 g of Tefose™ 63 (PEG-& glycol & PEG-32 Stearate), 1760 g ofcetostearyl alcohol, NF, 1540 g of triglycerides medium chain, NF(caprylic capric triglycerides), 1540 g of diisopropyl adipate, 1540 gof oleyl alcohol, NF, 440 g of lanolin, USP, 440 g of macrogol (6)cetostearyl ether (Cremophor A-6), Ph Eur, and 440 g of macrogol (25)cetostearyl ether (Cremophor A-25), Ph Eur was added, and the mixturewas heated to 73° C. to 75° C. while mixing at a low mixing speed (50rpm).

While the oil phase was melting, oxymetazoline hydrochloride, USP wasdissolved into Solution 2 to create the aqueous phase, and evaporatedwater was replaced by adding 10.9 g of purified water to the stainlesssteel beaker. Solution 1 was then added to the aqueous phase while thetemperature was maintained at 75° C. to 78° C. with low speed mixing(250 rpm). The resulting aqueous phase solution was than added at amoderate speed to the oil phase in the reactor vessel, preferably ananchor-type, propeller-equipped reactor vessel, with low speed mixing(50 rpm), and stirring was continued until the temperature in thereactor was 40° C. The mixing speed was then lowered to 30 rpm, and thetemperature was reduced to 35° C. When 35° C. was reached, the mixingspeed was again lowered to 20 rpm. The resulting white cream wasmanually discharged from the reactor and stored in a two 12 L stainlesssteel beakers.

TABLE 1 COMPOSITION OF OXYMETAZOLINE CREAM TRIAL 36 Amount perIngredient % W/W Batch (g) Oxymetazoline hydrochloride, USP 0.01 2.22-Phenoxyethanol, Ph Eur 0.80 176 Methylparaben, NF 0.20 44Propylparaben, NF 0.05 11 Edetate Disodium, Dihydrate, USP 0.01 2.2Butylated Hydroxytoluene, NF 0.05 11 Polyethylene Glycol 300, NF 4.0 880Tefose 63 8.0 1760 Cetostearyl alcohol, NF 8.0 1760 Triglycerides mediumchain, NF 7.0 1540 (caprylic capric/triglycerides) Diisopropyl adipate7.0 1540 Oleyl alcohol, NF 7.0 1540 Lanolin, USP 2.0 440 Cremophor A-62.0 440 Cremophor A-25 2.0 440 Purified Water, USP (1) 51.38 11305.8Purified Water, USP (2) QS QS Anhydrous Citric Acid, USP 0.20 44 SodiumCitrate Dihydrate, USP 0.30 66

TABLE 2 COMPOSITION OF OXYMETAZOLINE CREAM TRIAL 36 % W/W IngredientsFunction QS Oxymetazoline Hydrochloride, Active USP 0.80 Phenoxyethanol,Ph Eur Antimicrobial preservative 0.20 Methylparaben, NF Antimicrobialpreservative 0.05 Propylparaben, NF Antimicrobial preservative 0.01Disodium Edetate, USP Chelating agent 0.05 Butylated Hydroxytoluene, NFAnti-oxidant 4.00 Polyethylene Glycol 300, NF Humectant 5.00 PEG-6Stearate Emulsifier 1.50 Glycol Stearate Emulsifier 1.50 PEG-32 StearateEmulsifier 8.00 Cetostearyl alcohol, NF Emollient, stiffening agent andemulsion stabilizer 7.00 Triglycerides medium chain, NF Emollient, oilcomponent (Caprylic capric triglycerides) 7.00 Diisopropyl adipateEmollient, oil component 7.00 Oleyl Alcohol, NF Emollient, oil component2.00 Lanolin, USP Emollient, oil component 2.00 Macrogol (6) CetostearylEther Non-ionic o/w emulsifier, (Cremophor A-6), Ph Eur consistencyenhancer 2.00 Macrogol (25) Cetostearyl Ether Non-ionic o/w emulsifier,(Cremophor A-25), Ph Eur consistency enhancer 51.38 Purified Water, USPVehicle 0.20 Anhydrous Citric Acid, USP Buffering agent 0.30 SodiumCitrate Dihydrate, USP Buffering agent 100.00

Example 2

Oxymetazoline creams having a variety of formulations were prepared asdescribed in Example 1 in order to obtain a cream which was cosmeticallyacceptable and had enough consistency to support prolonged exposure at40° C. without losing its physical integrity. Trial 1 was a baseformulation without any API. Trial 2 included 0.1% API to determine theimpact that the API would have on the base formulation. The consistency(Viscosity value) revealed that there was no immediate physical impactof the active at 0.1% concentration on the physical integrity of thecream base as compared to the plain base in Trial 1. Trials 3, 5 and 6were formulations prepared during development work. Trials 7-11 wereformulations prepared for the first stability study. Trials 12-13 wereformulations containing higher concentrations of oxymetazoline (2% and1%, respectively). Trials 15-18 were formulations made for toxicologystudies. Batches A and B were the same and were combined to make alarger batch for the toxicology studies. Trial 19 was a formulationwithout preservatives for analytical method development. Trials 20-34were the first round of optimization formulations. Trials 35-37 werebuffered at pH 4.5 and included a high content of cetostearyl alcoholand Tefose™ 63. Trials 38-41 further optimized the Trial 36 formulationwith 0.5%, 1%, 2% API and a placebo. Trials 42-43 further optimized theTrial 36 formulation with 0.01%, and 0.15% API and were used in thepermeation flux studies. Trial 45 was a large engineering batch of theTrial 36 formulation. Trial 46-48 and 51 were made for analytical methoddevelopment. Trials 49-50 were made for toxicology studies and contain0.05% and 0% API, respectively.

TABLE 3 PREPARATION OF OXYMETAZOLINE CREAM: TRIALS 1-7A (% W/W) Trial 1Trial 2 Trial 3 Trial 4 Trial 5 Trial 6 Trial 7 Trial 7A OxymetazolineHCl 0.000 0.100 0.025 NA 0.100 0.050 0.150 0.025 Phenoxyethanol 0.8000.800 0.800 NA 0.800 0.800 0.800 0.800 Methylparaben 0.200 0.200 0.200NA 0.200 0.200 0.200 0.200 Propylparaben 0.050 0.050 0.050 NA 0.0500.050 0.050 0.050 Disodium Edetate 0.010 0.010 0.010 NA 0.010 0.0100.010 0.010 Butylated Hydroxytoluene 0.050 0.050 0.050 NA 0.050 0.0500.050 0.050 Polyethylene Glycol 300 4.000 4.000 4.000 NA 4.000 4.0004.000 4.000 Tefose 63 7.500 7.500 8.000 NA 8.000 8.000 8.000 8.000Cetostearyl alcohol 4.000 4.000 5.000 NA 5.000 5.000 5.000 5.000Triglycerides medium chain 7.000 7.000 7.000 NA 7.000 7.000 7.000 7.000Diisopropyl adipate 7.000 7.000 7.000 NA 7.000 7.000 7.000 7.000 OleylAlcohol 7.000 7.000 7.000 NA 7.000 7.000 7.000 7.000 Lanolin 2.000 2.0002.000 NA 2.000 2.000 2.000 2.000 Macrogol (6) Cetostearyl 2.000 2.0002.000 NA 2.000 2.000 2.000 2.000 Ether Macrogol (25) Cetostearyl 2.0002.000 2.000 NA 2.000 2.000 2.000 2.000 Ether Anhydrous Citric Acid 0.0000.000 0.000 NA 0.000 0.000 0.000 0.000 Sodium Citrate Dihydrate 0.0000.000 0.000 NA 0.000 0.000 0.000 0.000 Hydroxyethyl Cellulose 0.0000.000 0.000 NA 0.000 0.000 0.000 0.000 Lipoid S-75 0.000 0.000 0.000 NA0.000 0.000 0.000 0.000 Trizma 0.000 0.000 0.000 NA 0.000 0.000 0.0000.000 Purified Water 56.390 56.290 54.865 NA 54.790 54.840 54.740 54.865

TABLE 4 PREPARATION OF OXYMETAZOLINE CREAM: TRIALS 8-15A (% W/W) TrialTrial Trial Trial Trial Trial Trial 8 Trial 9 10 11 12 13 14 15AOxymetazoline HCl 0.100 0.050 0.150 0.010 2.000 1.000 NA 2.000Phenoxyethanol 0.800 0.800 0.800 0.800 0.800 0.800 NA 0.800Methylparaben 0.200 0.200 0.200 0.200 0.200 0.200 NA 0.200 Propylparaben0.050 0.050 0.050 0.050 0.050 0.050 NA 0.050 Disodium Edetate 0.0100.010 0.010 0.010 0.010 0.010 NA 0.010 Butylated Hydroxytoluene 0.0500.050 0.050 0.050 0.050 0.050 NA 0.050 Polyethylene Glycol 300 4.0004.000 4.000 4.000 4.000 4.000 NA 4.000 Tefose 63 8.000 8.000 8.000 8.0008.000 8.000 NA 8.000 Cetostearyl alcohol 5.000 5.000 5.000 5.000 5.0005.000 NA 5.000 Triglycerides medium chain 7.000 7.000 7.000 7.000 7.0007.000 NA 7.000 Diisopropyl adipate 7.000 7.000 7.000 7.000 7.000 7.000NA 7.000 Oleyl Alcohol 7.000 7.000 7.000 7.000 7.000 7.000 NA 7.000Lanolin 2.000 2.000 2.000 2.000 2.000 2.000 NA 2.000 Macrogol (6)Cetostearyl 2.000 2.000 2.000 2.000 2.000 2.000 NA 2.000 Ether Macrogol(25) Cetostearyl 2.000 2.000 2.000 2.000 2.000 2.000 NA 2.000 EtherAnhydrous Citric Acid 0.000 0.000 0.000 0.000 0.000 0.000 NA 0.000Sodium Citrate Dihydrate 0.000 0.000 0.000 0.000 0.000 0.000 NA 0.000Hydroxyethyl Cellulose 0.000 0.000 0.000 0.000 0.000 0.000 NA 0.000Lipoid S-75 0.000 0.000 0.000 0.000 0.000 0.000 NA 0.000 Trizma 0.0000.000 0.000 0.000 0.000 0.000 NA 0.000 Purified Water 54.790 54.84054.740 54.880 52.890 53.890 NA 52.890

TABLE 5 PREPARATION OF OXYMETAZOLINE CREAM: TRIALS 15B-19 (% W/W) TrialTrial Trial Trial Trial Trial Trial Trial 15B 16A 16B 17A 17B 18A 18B 19Oxymetazoline HCl 2.000 1.000 1.000 0.500 0.500 0.000 0.000 0.150Phenoxyethanol 0.800 0.800 0.800 0.800 0.800 0.800 0.800 0.000Methylparaben 0.200 0.200 0.200 0.200 0.200 0.200 0.200 0.000Propylparaben 0.050 0.050 0.050 0.050 0.050 0.050 0.050 0.000 DisodiumEdetate 0.010 0.010 0.010 0.010 0.010 0.010 0.010 0.010 ButylatedHydroxytoluene 0.050 0.050 0.050 0.050 0.050 0.050 0.050 0.050Polyethylene Glycol 300 4.000 4.000 4.000 4.000 4.000 4.000 4.000 4.000Tefose 63 8.000 8.000 8.000 8.000 8.000 8.000 8.000 8.000 Cetostearylalcohol 5.000 5.000 5.000 5.000 5.000 5.000 5.000 5.000 Triglyceridesmedium chain 7.000 7.000 7.000 7.000 7.000 7.000 7.000 7.000 Diisopropyladipate 7.000 7.000 7.000 7.000 7.000 7.000 7.000 7.000 Oleyl Alcohol7.000 7.000 7.000 7.000 7.000 7.000 7.000 7.000 Lanolin 2.000 2.0002.000 2.000 2.000 2.000 2.000 2.000 Macrogol (6) Cetostearyl Ether 2.0002.000 2.000 2.000 2.000 2.000 2.000 2.000 Macrogol (25) Cetostearyl2.000 2.000 2.000 2.000 2.000 2.000 2.000 2.000 Ether Anhydrous CitricAcid 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 Sodium CitrateDihydrate 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 HydroxyethylCellulose 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 Lipoid S-750.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 Trizma 0.000 0.000 0.0000.000 0.000 0.000 0.000 0.000 Purified Water 52.890 53.890 53.890 54.39054.390 54.890 54.890 55.790

TABLE 6 PREPARATION OF OXYMETAZOLINE CREAM: TRIALS 20-27 (% W/W) TrialTrial Trial Trial Trial Trial Trial Trial 20 21 22 23 24 25 26 27Oxymetazoline HCl 0.010 0.150 0.010 0.010 0.010 0.010 0.010 0.010Phenoxyethanol 0.800 0.800 0.800 0.800 0.800 0.800 0.800 0.800Methylparaben 0.200 0.200 0.200 0.200 0.200 0.200 0.200 0.200Propylparaben 0.050 0.050 0.050 0.050 0.050 0.050 0.050 0.050 DisodiumEdetate 0.010 0.010 0.010 0.010 0.010 0.010 0.010 0.010 ButylatedHydroxytoluene 0.050 0.050 0.050 0.050 0.050 0.050 0.050 0.050Polyethylene Glycol 300 4.000 4.000 4.000 4.000 4.000 4.000 4.000 4.000Tefose 63 8.000 8.000 8.000 8.000 8.000 8.000 10.000 10.000 Cetostearylalcohol 5.000 5.000 5.000 5.000 5.000 5.000 8.000 10.000 Triglyceridesmedium chain 7.000 7.000 7.000 7.000 7.000 7.000 7.000 7.000 Diisopropyladipate 7.000 7.000 7.000 7.000 7.000 7.000 7.000 7.000 Oleyl Alcohol7.000 7.000 7.000 7.000 7.000 7.000 7.000 7.000 Lanolin 2.000 2.0002.000 2.000 2.000 2.000 2.000 2.000 Macrogol (6) Cetostearyl Ether 2.0002.000 2.000 2.000 2.000 2.000 2.000 2.000 Macrogol (25) Cetostearyl2.000 2.000 2.000 2.000 2.000 2.000 2.000 2.000 Ether Anhydrous CitricAcid 0.000 0.000 0.200 0.000 0.100 0.200 0.000 0.000 Sodium CitrateDihydrate 0.000 0.000 0.300 0.000 0.450 0.300 0.000 0.000 HydroxyethylCellulose 0.000 0.000 0.000 0.500 0.000 0.500 0.000 0.000 Lipoid S-750.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 Trizma 0.000 0.000 0.0000.000 0.000 0.000 0.000 0.000 Purified Water 54.880 54.740 54.380 54.38054.330 53.880 49.880 47.880

TABLE 7 PREPARATION OF OXYMETAZOLINE CREAM: TRIALS 28-35 (% W/W) TrialTrial Trial Trial Trial Trial Trial Trial 28 29 30 31 32 33 34 35Oxymetazoline HCl 0.010 0.010 0.010 0.010 0.010 0.150 0.150 0.010Phenoxyethanol 0.800 0.800 0.800 0.800 0.800 0.800 0.800 0.800Methylparaben 0.200 0.200 0.200 0.200 0.200 0.200 0.200 0.200Propylparaben 0.050 0.050 0.050 0.050 0.050 0.050 0.050 0.050 DisodiumEdetate 0.010 0.010 0.010 0.010 0.010 0.010 0.010 0.010 ButylatedHydroxytoluene 0.050 0.050 0.050 0.050 0.050 0.050 0.050 0.050Polyethylene Glycol 300 4.000 4.000 4.000 4.000 4.000 4.000 4.000 4.000Tefose 63 8.000 8.000 8.000 8.000 8.000 8.000 8.000 10.000 Cetostearylalcohol 5.000 5.000 5.000 5.000 5.000 5.000 5.000 10.000 Triglyceridesmedium chain 3.500 10.500 7.000 7.000 7.000 3.500 10.500 7.000Diisopropyl adipate 3.500 10.500 7.000 7.000 7.000 3.500 10.500 7.000Oleyl Alcohol 14.000 0.000 0.000 0.000 7.000 14.000 0.000 7.000 Lanolin2.000 2.000 2.000 2.000 2.000 2.000 2.000 2.000 Macrogol (6) Cetostearyl2.000 2.000 2.000 2.000 1.000 2.000 2.000 2.000 Ether Macrogol (25)Cetostearyl 2.000 2.000 2.000 2.000 1.000 2.000 2.000 2.000 EtherAnhydrous Citric Acid 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.200Sodium Citrate Dihydrate 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.300Hydroxyethyl Cellulose 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000Lipoid S-75 0.000 0.000 2.000 0.000 0.000 0.000 0.000 0.000 Trizma 0.0000.000 0.000 0.000 0.000 0.000 0.000 0.000 Purified Water 54.880 54.88059.880 61.880 56.880 54.740 54.740 47.380

TABLE 8 PREPARATION OF OXYMETAZOLINE CREAM: TRIALS 36-40A (% W/W) TrialTrial Trial Trial Trial Trial Trial Trial 36 37 38 38A 39 39A 40 40AOxymetazoline HCl 0.010 0.010 0.000 0.000 0.500 0.500 1.000 1.000Phenoxyethanol 0.800 0.800 0.800 0.800 0.800 0.800 0.800 0.800Methylparaben 0.200 0.200 0.200 0.200 0.200 0.200 0.200 0.200Propylparaben 0.050 0.050 0.050 0.050 0.050 0.050 0.050 0.050 DisodiumEdetate 0.010 0.010 0.010 0.010 0.010 0.010 0.010 0.010 ButylatedHydroxytoluene 0.050 0.050 0.050 0.050 0.050 0.050 0.050 0.050Polyethylene Glycol 300 4.000 4.000 4.000 4.000 4.000 4.000 4.000 4.000Tefose 63 8.000 9.000 8.000 8.000 8.000 8.000 8.000 8.000 Cetostearylalcohol 8.000 7.000 8.000 8.000 8.000 8.000 8.000 8.000 Triglyceridesmedium chain 7.000 7.000 7.000 7.000 7.000 7.000 7.000 7.000 Diisopropyladipate 7.000 7.000 7.000 7.000 7.000 7.000 7.000 7.000 Oleyl Alcohol7.000 7.000 7.000 7.000 7.000 7.000 7.000 7.000 Lanolin 2.000 2.0002.000 2.000 2.000 2.000 2.000 2.000 Macrogol (6) Cetostearyl 2.000 2.0002.000 2.000 2.000 2.000 2.000 2.000 Ether Macrogol (25) Cetostearyl2.000 2.000 2.000 2.000 2.000 2.000 2.000 2.000 Ether Anhydrous CitricAcid 0.200 0.200 0.200 0.200 0.200 0.200 0.200 0.200 Sodium CitrateDihydrate 0.300 0.300 0.300 0.300 0.300 0.300 0.300 0.300 HydroxyethylCellulose 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 Lipoid S-750.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 Trizma 0.000 0.000 0.0000.000 0.000 0.000 0.000 0.000 Purified Water 51.380 51.380 51.390 51.39050.890 50.890 50.390 50.390

TABLE 9 PREPARATION OF OXYMETAZOLINE CREAM: TRIALS 41-47 (% W/W) TrialTrial Trial Trial Trial Trial Trial Trial 41 41A 42 43 44 45 46 47Oxymetazoline HCl 2.000 2.000 0.010 0.150 NA 0.000 0.500 0.250Phenoxyethanol 0.800 0.800 0.800 0.800 NA 0.800 0.800 0.800Methylparaben 0.200 0.200 0.200 0.200 NA 0.200 0.200 0.200 Propylparaben0.050 0.050 0.050 0.050 NA 0.050 0.050 0.050 Disodium Edetate 0.0100.010 0.010 0.010 NA 0.010 0.010 0.010 Butylated Hydroxytoluene 0.0500.050 0.050 0.050 NA 0.050 0.050 0.050 Polyethylene Glycol 300 4.0004.000 4.000 4.000 NA 4.000 4.000 4.000 Tefose 63 8.000 8.000 8.000 8.000NA 8.000 8.000 8.000 Cetostearyl alcohol 8.000 8.000 8.000 8.000 NA8.000 8.000 8.000 Triglycerides medium chain 7.000 7.000 7.000 7.000 NA7.000 7.000 7.000 Diisopropyl adipate 7.000 7.000 7.000 7.000 NA 7.0007.000 7.000 Oleyl Alcohol 7.000 7.000 7.000 7.000 NA 7.000 7.000 7.000Lanolin 2.000 2.000 2.000 2.000 NA 2.000 2.000 2.000 Macrogol (6)Cetostearyl Ether 2.000 2.000 2.000 2.000 NA 2.000 2.000 2.000 Macrogol(25) Cetostearyl 2.000 2.000 2.000 2.000 NA 2.000 2.000 2.000 EtherAnhydrous Citric Acid 0.200 0.200 0.200 0.200 NA 0.200 0.200 0.200Sodium Citrate Dihydrate 0.300 0.300 0.300 0.300 NA 0.300 0.300 0.300Hydroxyethyl Cellulose 0.000 0.000 0.000 0.000 NA 0.000 0.000 0.000Lipoid S-75 0.000 0.000 0.000 0.000 NA 0.000 0.000 0.000 Trizma 0.0000.000 0.000 0.000 NA 0.000 0.000 0.000 Purified Water 49.390 49.39051.380 51.240 NA 51.390 50.890 51.140

TABLE 10 PREPARATION OF OXYMETAZOLINE CREAM: TRIALS 48-51 (% W/W) Trial48 Trial 49 Trial 50 Trial 51 Oxymetazoline HCl 0.100 0.050 0.000 0.150Phenoxyethanol 0.800 0.800 0.800 0.800 Methylparaben 0.200 0.200 0.2000.200 Propylparaben 0.050 0.050 0.050 0.050 Disodium Edetate 0.010 0.0100.010 0.010 Butylated Hydroxytoluene 0.050 0.050 0.050 0.050Polyethylene Glycol 300 4.000 4.000 4.000 4.000 Tefose 63 8.000 8.0008.000 8.000 Cetostearyl alcohol 8.000 8.000 8.000 8.000 Triglyceridesmedium chain 7.000 7.000 7.000 7.000 Diisopropyl adipate 7.000 7.0007.000 7.000 Oleyl Alcohol 7.000 7.000 7.000 7.000 Lanolin 2.000 2.0002.000 2.000 Macrogol (6) Cetostearyl Ether 2.000 2.000 2.000 2.000Macrogol (25) Cetostearyl Ether 2.000 2.000 2.000 2.000 Anhydrous CitricAcid 0.200 0.200 0.200 0.000 Sodium Citrate Dihydrate 0.300 0.300 0.3000.000 Hydroxyethyl Cellulose 0.000 0.000 0.000 0.000 Lipoid S-75 0.0000.000 0.000 0.000 Trizma 0.000 0.000 0.000 0.000 Purified Water 51.29051.340 51.390 51.740

The purpose of this protocol was to perform a stability study onOxymetazoline Topical Creams, 0.05%, 0.10% and 0.15%. The creams werepackaged into two packaging configurations; 30-g polyethylene tubes and30-g glaminate tubes. Approximately 120 tubes of each creamconcentration were prepared. The creams were placed on stability for upto 36 months at the nominal storage condition of 25° C./60% RH and for 6months at accelerated conditions of 40° C./75% RH. Some samples werealso stored at the intermediate condition, 30° C./75% RH. The results ofthis stability study can be found in Tables 11-13. The pH of the productexhibited a tendency to decrease over time. This tendency appeared to bemore pronounced in the samples stored at 40° C./75% RH. The observedappearance of the product at 40° C./75% RH indicated that there was aportion of the cream that melted to the point of becoming a liquid. Bothof these issues represented a concern for the long term stability of thecream formulation. It is noted from the stand point of chemicalstability of the drug, there was no appreciable drop in potency andthere was a very low presence of impurities on the samples tested.

TABLE 11 STABILITY STUDY RESULTS - PRODUCT STORED IN POLYETHYLENE TUBES40°′ 40°′ 25°′ 30°′ C./75% C./75% C./60% C./65% Initial@Room RH,. 2 RH,.1 RH,. 1 RH,. 1 Parameters Temperature Weeks Month Month MonthOxymetazoline HCl Creams 0.01% Assay (% LC) 101.0 102.0 96.0 101.5 N/RpH 4.45 4.23 4.03 4.05 4.22 Oxymetazoline HCl Creams 0.05% Assay (% LC)104.3 101.3 101.3 101.8 100.6 CP (% Area) 0.5 0.6 0.3 0.4 N/R pH 4.294.16 3.98 4.09 4.14 Oxymetazoline HCl Creams 0.10%. Assay (% LC) 104.1104.5 106.8 101.6 101.8 CP (% Area) 0.3 0.4 0.1 0.2 N/R pH 4.39 4.223.98 4.05 4.11 Oxymetazoline HCl Creams 0.15% Assay (% LC) 100.9 99.2102.1 99.8 100.1 CP (% Area) 0.2 0.3 0.1 0.2 N/R pH 4.42 4.22 3.87 4.044.08 N/R = not reported

TABLE 12 STABILITY STUDY RESULTS - PRODUCT STORED IN GLAMINATE TUBESInitial@Room 40°′ C./75% Parameters Temperature RH,. 2 Weeks Avg % RSDOxymetazoline HCl Creams 0.01% Assay (% LC) 101.5 101.0 101.3 0.3 pH4.38 4.11 4.2 4.5 Oxymetazoline HCl Creams 0.05% Assay (% LC) 102.8105.0 103.9 1.5 CP (% Area) 0.7 0.8 NA NA pH 4.12 4.01 4.1 1.9Oxymetazoline HCl Creams 0.10%. Assay (% LC) 102.1 104.0 103.1 1.3 CP (%Area) 0.5 0.5 NA NA pH 4.13 4.01 4.1 2.1 Oxymetazoline HCl Creams 0.15%Assay (% LC) 100.2 101.4 100.8 0.8 CP (% Area) 0.4 0.3 NA NA pH 4.103.98 4.0 2.1 The appearance of the samples stored for 1 month at 30° C.is within specification (White viscous cream); the homogeneous creamsare similar to the samples stored at 25° C.

TABLE 13 STABILITY STUDY RESULTS - APPEARANCE OF PRODUCT IN POLYETHYLENETUBES AND GLAMINATE TUBES Sample Description Condition AppearancePolyethylene Tubes Oxymetazoline HCl Creams 25° C./60% RH, White viscouscream 0.01% 1 Month Oxymetazoline HCl Creams 25° C./60% RH, Whiteviscous cream 0.05% 1 Month Oxymetazoline HCl Creams 25° C./60% RH,White viscous cream 0.10% 1 Month Oxymetazoline HCl Creams 25° C./60%RH, White viscous cream 0.15% 1 Month Glaminate tubes Oxymetazoline HClCreams 40° C./75% RH, White viscous cream (not homogeneous) 0.01% 1Month (A portion of the cream was transferred from the tube to a glassculture tube, a different consistency was observed) Oxymetazoline HClCreams 40° C./75% RH, White viscous cream (not homogeneous) 0.05% 1Month (A portion of the cream was transferred from the tube to a glassculture tube, a different consistency was observed) Oxymetazoline HClCreams 40° C./75% RH, White viscous cream (not homogeneous) 0.10% 1Month (A portion of the cream was transferred from the tube to a glassculture tube, a different consistency was observed) Oxymetazoline HClCreams 40° C./75% RH, White viscous cream (not homogeneous) 0.15% 1Month (A portion of the cream was transferred from the tube to a glassculture tube, a different consistency was observed)

Creams from Trials 20-34 were packaged into 30-g glaminate tubes. Thecreams were placed on stability for up to 4 weeks at storage conditionof 25° C./60% RH at accelerated conditions of 60° C. and 40° C./75% RHand at the intermediate condition 30° C./75% RH. Trials 20-34 weretested initially and after 1 week. Viscosity was measure using aBrookfield RVT, C/P, Spindle CPE-52, 25 rpm, RT. The results areoutlined in Table 14.

TABLE 14 STUDY RESULTS Viscosity pH pH Sample ID cPs (Initial) (1 week)²Appearance (Initial) Appearance (1 week)² Trial # 20 1836 4.45 4.58White Viscous Cream White Viscous Cream (Homogeneous) (Homogeneous) 4.32White Viscous Cream (Homogeneous) 4.16 White Viscous Cream (Homogeneous)Trial #21 2367 3.92 3.89 White Viscous Cream White Viscous Cream(Homogeneous) (Homogeneous) 3.74 White Viscous Cream (Homogeneous) 3.58White Viscous Cream (Homogeneous) Trial #22 3450 4.57 4.55 White ViscousCream White Viscous Cream (Homogeneous) (Homogeneous) 4.57 White ViscousCream (Homogeneous) 4.54 White Viscous Cream (Homogeneous) Trial #236895 4.24 4.15 White Viscous Cream White Viscous Cream (Homogeneous)(Homogeneous) 4.05 White Viscous Cream (Homogeneous) 3.93 White ViscousCream with oily spots Trial # 24 1608 5.58 5.51 White Viscous CreamWhite Viscous Cream (Homogeneous) (Homogeneous) 5.51 White Cream-Lotion5.48 White Viscous Cream (Homogeneous) Trial #25  19183¹  4.66 4.58White Viscous Cream White Viscous Cream (Homogeneous) (Homogeneous) 4.58White Viscous Cream (Homogeneous) 4.58 White Viscous Cream (Homogeneous)Trial #26  8458¹ 3.94 3.69 White Viscous Cream White Viscous Cream(Homogeneous) (Homogeneous) 3.72 White Viscous Cream (Homogeneous) 3.64White Viscous Cream (Homogeneous) Trial #27 21067  4.44 4.17 WhiteViscous Cream White Viscous Cream (Homogeneous) (Homogeneous) 4.04 WhiteViscous Cream (Homogeneous) 3.87 White Viscous Cream (Homogeneous) Trial#28 4695 4.61 4.54 White Viscous Cream White Viscous Cream (Homogeneous)(Homogeneous) 4.38 White Viscous Cream (Homogeneous) 4.18 White ViscousCream (Homogeneous) Trial #29 4686 4.53 4.41 White Viscous Cream WhiteViscous Cream (Homogeneous) (Homogeneous) 4.26 White Viscous Cream(Homogeneous) 4.23 White Cream-Lotion Trial #30 6931 3.64 3.65 Off-WhiteViscous Off-White Viscous Cream Cream (Homogeneous) (Homogeneous) 3.56Off-White Viscous Cream (Homogeneous) 3.55 Off-White Viscous Cream(Homogeneous) Trial #31 1700 5.65 5.50 White Viscous Cream White ViscousCream (Homogeneous) (Homogeneous) 5.36 White Viscous Cream (Homogeneous)5.04 White Cream-Lotion Trial #32 7269 3.75 3.69 White Viscous CreamWhite Viscous Cream (Homogeneous) (Homogeneous) 3.56 White soft Cream3.62 White Lotion Trial #33 2580 4.25 4.23 White Viscous Cream WhiteViscous Cream (Homogeneous) (Homogeneous) 4.07 White Cream-Lotion 3.87White Viscous Cream (Homogeneous) Trial #34 5639 4.09 4.03 White ViscousCream White Viscous Cream (Homogeneous) (Homogeneous) 3.95 WhiteCream-Lotion 3.84 White Cream-Lotion ¹Modified Method used Speed @10 RPM²Order: 25° C./60% RH 40° C./75%/RH 60° C.

Based on the stability studies of Trials 20-34, it appears that buffersystems stabilize the pH of the formulation. Formulations with highcontent of Cetostearyl Alcohol and Tefose™ 63 show a higher viscosityand a stable physical consistency when exposed to 60° C. temperature for1 week. While not wishing to be bound by theory, this may be explaineddue to the two excipients' wax-like consistency and as such they imparta more rigid structure to the cream. Further evaluation of the stabilitydata pointed to formulations which were optimized by buffers and higherwax-like material content. A buffer that could maintain a pH of about4.5 was selected for Trials 35-37.

Example 3

Oxymetazoline creams formulated as Trials 35-37 were filled into 30 gramtubes and stored at 25° C., 30° C., 40° C., and 60° C. Each cream wasinitially tested for appearance (Ap), melting point (mDSC), zetapotential (ZP), pH, and viscosity (V), and each sample was reevaluatedonce per week for 4 weeks to evaluate stability as follows:

Initial: Ap; mDSC; ZP; pH; and V

Week-1 (25; 40; 60): Ap; mDSC; ZP; pH; and V (if Ap passes)

Week-2 (25; 40): Ap; mDSC; ZP; pH; and V (if Ap passes)

Week-4 (25; 40): Ap; mDSC; pH; and V (if Ap passes)

A sensorial evaluation was conducted by a blinded panel. The panel'sevaluation of cosmetic acceptability was based on the criteria providedin Table 15:

TABLE 15 CRITERIA FOR COSMETIC ACCEPTABILITY EVALUATION Test CategoryScale General Appearance 7 = Pleasant 

 1 = Unpleasant Color 7 = Pleasant 

 1 = Unpleasant Smell 7 = Pleasant 

 1 = Unpleasant Tackiness 7 = Not Sticky 

 1 = Very Sticky Oiliness 7 = Not Oily 

 1 = Very Oily Cosmetic Elegance 7 = Very elegant 

 1 = Not Elegant Ease of Application 7 = Spreads Easily 

 1 = Not Well Speed of Absorption 7 = Very Quickly 

 1 = Very Slowly Overall Application 7 = Very Pleasant 

 1 = Very Unpleasant Irritation/Stinging 7 = Not Irritating 

 1 = Very Irritating Dry Skin 7 = Not Drying 

 1 = Very Drying Moisturizing 7 = Moisturizing 

 1 = Not Moisturizing Can I put Make-up 7 = Strongly Agree 

 1 = Strongly Disagree Over Cream Overall Impression 7 = ExcellentProduct 

 1 = Terrible Product

Mean scores by category are provided in FIG. 1, and the mean results forkey evaluation categories are provided in FIG. 2. The total mean scoreis provided in FIG. 3. As indicated in FIG. 1-3, each formulationexhibited acceptable appearance. Overall, the panel selected theformulation of Trial 36 as containing the best sensorial attributesaccording to the criteria under Table 15.

Tables 16 and 17 contain data on modulated Differential Scanningcalorimetry (mDSC) and Zeta Potential (ZP) determinations performed onsamples of the Trials 20 through 34 and for the three high wax contentformulations Trials 36, 37 and 38. Samples of the creams were subjectedto mDSC cycles of heating and cooling from about 7° C. to 60° C. andback. It was found that an optimal formulation combines a buffer systemat pH 4.5, such as Trial 22, with a high content of wax-like material(Cetostearyl alcohol and Tefose 63) which demonstrated a physicallystable formulation.

Confirmatory studies of mDSC and Zeta Potential were conducted on theformulation of Trial 36. The formulation of Trial 36 was compared withthe formulation of Trial 27. Results: Trial 36 formulation showed thatno major changes are taking place with respect to the compound structureuntil 42.5° C. except changes in physical properties of the materialafter 39° C. in first heat and after 33° C. in second heat. Trial 27formulation showed that the initial mDSC at 25° C. and after 1 week wereless stabile than the formulations of Trial 36. The physical changes arepresent from about 26° C. and the structural changes show an increasedactivity after about 40° C. At the same time, the plot of Trial 36formulation is very similar with the Trial 27 formulation plotted after1 week at 60° C. stability. The improvement in mDSC of Trial 36 appearsto be the combined result of adjusting the ratio of cetostearyl alcoholto Tefose™ 63 to 1:1, optimization of the concentrations of Tefose andcetostearyl alcohol, and optimization of the overall totalconcentrations and ratio of emulsifier to emollient.

The pH of Trial 36 was adjusted to 4.5 using anhydrous citric acid (0.2%by weight) and sodium citrate dihydrate (0.3% by weight), and the zetapotential of this formula was −5.

Example 4

The formulation of Trial 36 was selected for a formal acceleratedstability study. For this study Trials 42 at 0.01% API and Trial 43 at0.15% API were prepared. The purpose of this protocol was to perform astability study on Oxymetazoline Topical Creams, 0.01% and 0.15% basedon Trial 36. The creams were packaged into 30-g glaminate tubes.Approximately 60 tubes of each cream concentration was prepared. Thecreams were placed on stability at the nominal storage condition of 25°C./60% RH and at accelerated conditions of 40° C./75% RH. Samples werealso stored at the intermediate condition, 30° C./75% RH. Viscosity wasmeasured using a Brookfield RVT, C/P, Spindle CPE-52, 25 rpm, RT.

RESULTS: The appearance, viscosity, pH & assay results of the sampleswere consistent for the sub-samples from top, middle and bottom of thetube as well as the composite sample. This shows that the manufacturingprocedure was carried out efficiently. The results indicate thepreparation to be a stable formulation.

Example 5

An in vitro permeation procedure for oxymetazoline cream was developedusing the 0.01 and 0.10% w/w oxymetazoline cream. The in vitroexperiments were conducted using Hanson Microette Franz Cell apparatusand 0.01N PBS (pH 7.4) as the receiving medium. Other criticalparameters were evaluated such as the type of semi-synthetic membrane,sample timing (time dependent release-permeability profile), methodsensitivity, specificity and linearity.

Permeation characterization of oxymetazoline cream of differentstrengths (0.01% w/w, 0.05% w/w, 0.10% w/w and 0.15% w/w) was based onflux study across two different artificial membranes (cellulose acetateand polysulfone). The concentration of oxymetazoline which permeatedthrough the membranes was measured using an HPLC assay.

RESULTS: The oxymetazoline permeation rate over the concentration rangestudied exhibited a dump and die profile, reaching a peak after 0.5hours of the cream application. After this period, the drug releasegradually declined for the next 24 hours. Oxymetazoline permeability(AUC_(0-24 h)) linearly increased in the concentration range 0.01-0.10%w/w. Further increase of drug concentration (0.10-0.15% w/w), did notlead to a proportional increase in the amount of drug delivered acrossthe membrane. The in vitro membrane transport reached saturation abovethe 0.1% w/w level irrespective the membrane type used.

Permeability efficiency across the cellulose acetate and polysulfonemembranes (expressed as a percent of total drug permeated as a functionof time) was similar for all four strengths (30-40%) after the 24 hoursapplication period. Lower oxymetazoline release was observed in the caseof polysulfone at the lowest 0.01% w/w level. Without wishing to bebound by theory, this effect may be caused by drug binding to thismembrane at this low concentration level.

Example 6

Additional formulations were made using Trial 38 as the base formulationand varying the amount of oxymetazoline. Such formulations includedoxymetazoline at 0.01%, 0.05%, 0.06%, 0.1%, 0.15%, 0.25%, 0.5%, 1% and2.5%, and were found to be stable.

Example 7

A randomized, double-blind, vehicle-controlled, parallel group study ofthe dose-response profile of Trial 38 formulation was conducted insubjects with erythematous rosacea.

OBJECTIVE: the main objective was to evaluate the dose-responserelationship of 4 oxymetazoline concentrations of Trial 38 formulationand a matching vehicle cream when applied to the face. A furtherobjective was to evaluate the safety and efficacy of such formulationswhen applied to the face for 28 consecutive days. A further objectivewas to evaluate the time course, duration and magnitude of the clinicalresponse on the erythema of rosacea when such formulations are appliedto the face for 28 consecutive days. A further objective was to evaluatethe response of telangiectasias, the “clinician's telangiectasiaassessment score,” the time course and duration of the clinical responseof the telangiectasias of rosacea when such formulations are applied tothe face for 28 consecutive days.

METHODS: This was a randomized, double-blind, vehicle-controlled,parallel-group study of the Trial 38 base formulation with 0.01%, 0.06%,0.10%, and 0.15% oxymetazoline and the Trial 38 formulation with nooxymetazoline (vehicle) in subjects with stable moderate to severeerythematous rosacea. Approximately 175 subjects (35 per treatmentgroup) were planned; 183 subjects were randomized and applied studymedication. Subjects included males and females age 18 years in goodgeneral health with a clinical diagnosis of stable erythematous rosacea.Inclusion criteria included Subject's Self-Assessment (SSA) andClinician's Erythema Assessment (CEA) scores of ≧3, ≧3 inflammatorylesions (papules and/or pustules) and no cysts within the treatmentarea. SSA and CEA scores were graded on a 5-point ordinal scale (0=nosigns; 1=minimal; 2=mild; 3=moderate; and 4=severe).

Eligibility of subjects was determined during Visit 1. During Visit 2,eligible subjects were randomized and began a 28-day treatment period,which included Visit 3 on Day 14 and Visit 4 on Day 28. The treatmentperiod was followed by a 7-day no-treatment follow-up period, with Visit5 on Day 35, at the end of the study. On days between Visit 2 and Visit4, subjects applied study medication once daily.

Efficacy was evaluated at the study visits by the subject using the5-point SSA scale and by the investigator using the 5-point CEA scale,the 5-point Clinician's Telangiectasia Assessment (CTA) scale (0=nosigns; 1=minimal; 2=mild; 3=moderate; and 4=severe), and lesion countsfor total inflammatory lesions. Inferential tests between treatmentgroups were performed using appropriate analysis of covariance (ANCOVA)models at each post-application assessment time. The primary efficacyanalyses were based on the change-from-baseline area under the curve(AUC) for CEA and SSA calculated across all post-baseline visits.Pairwise comparisons between each active treatment group and the vehiclegroup were performed.

Secondary efficacy analyses characterized the effect of each treatmenton the SSA and CEA over the duration of a visit. Mean changes from eachvisit pre-application to each post-application assessment were evaluatedusing ANCOVA models including pairwise comparisons between each activetreatment group and the vehicle group. For SSA and CEA, subjects werealso classified at each post-application assessment as to treatmentsuccess on each of the parameters separately, where treatment successwas achieved if a subject had a score of <2 or a change from visit-daybaseline (Hour 0) of less than −1.

Safety was evaluated by treatment-emergent adverse events (TEAEs),laboratory evaluations, vital signs, and Irritation Signs and Symptoms(ISS).

RESULTS: A total of 183 subjects were randomized, 178 (97%) of whomcompleted the study. Overall 98.4% of subjects were white, 69.4% werefemale, and age ranged from 21 to 83 years (mean 51.2).

Efficacy: For CEA, both the 0.10% and 0.15% groups had statisticallysignificantly greater reductions than the vehicle group in AUC over Days0 to 28 (−14.162 and −13.103 vs −7.456, respectively; p<0.004). The0.10% and 0.15% groups had greater reductions in AUC than the 0.01% and0.06% groups (−8.250 and −10.181, respectively), which both hadnumerically greater reductions than the vehicle group.

Among the secondary efficacy analyses, change from baseline in CEA byvisit showed statistically significantly greater reductions(improvement) with 0.10% than vehicle on Day 0 at 3, 4, 6, and 8 hours;Day 14 at 3, 4, and 8 hours; and Day 28 at 8 hours, and with 0.15% onDay 0 at 3, 6, and 8 hours. There was a statistically significantlyhigher success rate with 0.10% and 0.15% than vehicle at 2 or 3 timepoints on Day 0.

As evaluated by the SSA, the AUC showed a greater reduction with 0.10%and 0.15% than with vehicle but the differences were not statisticallysignificant. Consistent improvement was seen with oxymetazolineformulations in secondary efficacy analyses of CEA and SSA, with somestatistically significant differences between oxymetazoline formulationgroups and the vehicle group (particularly on Day 0 and at 8 hours onDay 28).

Pre-dose CTA results on Days 0, 14, 28, and results on Day 35 aresummarized in Table 7. Change from baseline in CTA by visit showed astatistically significantly greater reduction (improvement) with theoxymetazoline formulations than with the vehicle (or improvementcompared to worsening with the vehicle) for the 0.10% group on Day 0 at6 hours and Day 28 at 8 hours, and for the 0.15% group on Day 28 at 1,2, and 8 hours (Table 7; FIG. 4).

TABLE 16 Clinician's Telangiectasia Assessment: Baseline and Mean Changefrom Baseline Mean (Standard Deviation) V-101 V-101 Vehicle 0.10% 0.15%Time (N = 37) (N = 37) (N = 35) Day 0 Baseline 1.973 (1.093)  2.459(1.016) 1.743 (1.245) 1 hour change  0.027 (0.440) −0.108 (0.567) 0.057(0.338) 2 hours change 0.054 (0.575) −0.189 (0.701) 0.171 (0.514) 3hours change −0.027 (0.552)  −0.351 (0.716) 0.029 (0.568) 4 hours change−0.081 (0.493)  −0.243 (0.760) 0.143 (0.601) 6 hours change 0.000(0.333)  −0.378 (0.758)* 0.057 (0.539) 8 hours change −0.027 (0.687) −0.324 (0.709) 0.057 (0.482) Day 28 Baseline 1.917 (1.228)  2.118(1.274) 1.882 (1.200) 1 hour change  0.139 (0.639)  0.029 (0.388) −0.118(0.478)* 2 hours change 0.083 (0.604)  0.029 (0.521) −0.294 (0.579)* 3hours change 0.056 (0.715) −0.118 (0.591) −0.176 (0.576)  4 hours change0.028 (0.845) −0.147 (0.657) −0.118 (0.478)  6 hours change 0.028(0.696) −0.118 (0.478) −0.088 (0.452)  8 hours change 0.056 (0.532) −0.206 (0.538)* −0.235 (0.431)* CTA scale: 0 = clear skin with no signsof telangiectasia; 1 = almost clear, a few barely visibletelangiectasia; 2 = mild, a few visible telangiectasia; 3 = moderate,with the presence of clearly visible telangiectasia; 4 = severe, withthe presence of many visible telangiectasia *p < 0.0500

Maintenance of clinical effect and no rebound was observed at day 35after discontinuing daily application of oxymetazoline creamcompositions after 28 days. The improvement in erythema was maintainedfor at least 7 days after discontinuation of drug application. Notachyphylaxis or rebound were observed.

Safety: There was no apparent relationship between the concentration ofoxymetazoline and the incidence of TEAEs overall or for any individualTEAE. Most TEAEs were mild or moderate in severity and considered notrelated to study medication.

CONCLUSION: Both the 0.10% and 0.15% oxymetazoline cream formulationsshowed a statistically significant better response than vehicle and abetter response than the lower concentrations on the primary efficacyendpoint of CEA as evaluated by the change-from-baseline AUC from Day 0to Day 28. In addition, there were a number of statistically significantresults for the 0.10% and 0.15% concentrations among the secondaryefficacy analyses. Specifically, the 0.15% concentration showedstatistically significant reductions in Clinician's TelangiectasiaGrading scores at hours 3, 4 and 8 on Day 28.

Example 8

Inflammatory lesion study: Subject was a 48 year old male with a 12 yearhistory of rosacea characterized by persistent episodes of facialerythema and inflammatory papules and pustules. The subject applied thetopical composition of 0.15% oxymetazoline cream once daily to the faceand noted both improvement in the erythema and a dramatic decrease ininflammatory lesions (papules and pustules). Daily use of thepreparation resulted in complete clearing of all inflammatory lesionswithin 3 weeks, and the improvement was maintained with continued dailyuse. Upon discontinuation of daily application, a maintenance of theimprovement was reported to continue for 4 weeks, after which time theinflammatory lesions gradually recurred. Upon rechallenge with the 0.15%oxymetazoline cream, the inflammatory lesions graduallyreturned/regressed.

Example 9

A double-blind, randomized, 2-way crossover study of V-101 cream 0.50%and oxymetazoline nasal spray 0.05% administered in adult subjects withmoderate to severe erythematous rosacea was conducted. The objectives ofthis study were to assess the relative bioavailability of a singleadministration of V-101 cream 0.50% and oxymetazoline nasal spray 0.05%(3 sprays) and to evaluate the safety of V-101 cream 0.50%.

A total of 28 subjects ranging in age from 22-63 years of age completedthe trial

TABLE 17 Subject Demographics Sequence 1 (AB) Sequence 2 (BA) TotalCharacteristic (N = 14) (N = 14) (N = 28) Age, years Mean (SD) 43.6(10.5) 41.8 (10.7) 42.7 (10.4) Range 25-63 22-60 22-63 Gender, N Male 4(28.6%) 5 (35.7%) 9 (32.1%) Female 10 (71.4%) 9 (64.3%) 19 (67.9%) Race,N White 14 (100%) 14 (100%) 28 (100%) Note: For sequences AB and BA, A =V-101 cream 0.50% + control (normal saline) nasal spray and B = vehiclecream + oxymetazoline 0.05% nasal spray; SD = standard deviation

At Treatment Visit 1 subjects were treated with one 0.5 g facialapplication of V 101 cream 0.50% plus 3 sprays of control (normalsaline) nasal spray in each nostril (Treatment A) or one 0.5 g facialapplication of vehicle cream plus 3 sprays of oxymetazoline nasal spray0.05% in each nostril (Treatment B). The treatment sequence (A then B orB then A) was randomized. Subjects received the opposite treatment atTreatment Visit 2. Evaluations and blood sampling for determination ofplasma concentrations of oxymetazoline took place through 12 hours afterdosing at each treatment visit.

Greater improvement in erythema, which was clinically and statisticallysignificant, was seen following treatment with V-101 cream 0.50% andcontrol nasal spray compared to that following treatment with vehiclecream and oxymetazoline nasal spray 0.05% as measured by both thesubject self assessment and the clinician erythema assessment startingat 2 hours and continuing through the completion of the study at 12hours postdose.

TABLE 18 Clinician's Erythema Assessment: Mean Predose and Mean Changefrom Predose for Subjects Completing the Study (Treatment SequencesCombined) Mean (Standard Deviation) V-101 Cream + Vehicle Cream +Control Spray Oxy 0.05% Spray Time (N = 28) (N = 28) P-value^(a) Predose 3.214 (0.418)  3.214 (0.418) NA 2 Hours Change −1.214 (0.833) −0.143(0.448) <0.001 3 Hours Change −1.571 (0.920) −0.036 (0.331) <0.001 4Hours Change −1.036 (0.793) −0.036 (0.189) <0.001 6 Hours Change −0.893(0.832)  0.000 (0.272) <0.001 9 Hours Change −0.500 (0.694) −0.036(0.189) <0.001 12 Hours Change  −0.286 (0.460)  0.000 (0.272) 0.003 AvgHours 3 to 6 −1.107 (0.832) −0.036 (0.189) <0.001 Change Avg = average,NA = not applicable, Oxy = oxymetazoline ^(a)P-values were calculatedusing analysis of covariance based on change from predose and variableswere analyzed as continuous variables.

TABLE 19 Subject's Self-Assessment: Mean Predose and Mean Change fromPredose for Subjects Completing the Study (Treatment Sequences Combined)Mean (Standard Deviation) V-101 Cream + Vehicle Cream + Control SprayOxy 0.05% Spray Time (N = 28) (N = 28) P-value^(a) Predose  3.071(0.262) 3.107 (0.315) NA 2 Hours Change −0.500 (0.638) 0.000 (0.000)<0.001 3 Hours Change −0.607 (0.629) 0.036 (0.189) <0.001 4 Hours Change−0.643 (0.731) 0.036 (0.189) <0.001 6 Hours Change −0.643 (0.731) 0.036(0.189) <0.001 9 Hours Change −0.607 (0.737) 0.036 (0.189) <0.001 12Hours Change  −0.607 (0.786) 0.036 (0.189) <0.001 Avg Hours 3 to 6−0.643 (0.731) 0.036 (0.189) <0.001 Change Avg = average, NA = notapplicable, Oxy = oxymetazoline ^(a)P-values were calculated usinganalysis of covariance based on change from predose and variables wereanalyzed as continuous variables.

In conclusion, a single topical facial administration of V-101 cream0.50% under maximum use conditions in subjects with moderate to severeerythematous rosacea resulted in minimal systemic exposure when comparedwith a single administration of Afrin Nasal Spray 0.05%. Topical facialapplication of V 101 cream 0.50% was well tolerated and significantlyreduced erythema from 2 to 12 hours postdose.

The study demonstrated the safety of a single, maximum use facialapplication of V 101 cream 0.50%. No adverse events considered to berelated to study medication were reported during the study.

Example 10

A randomized, double-blind, vehicle-controlled, parallel-group,multicenter study of 2 concentrations of V-101 cream (0.15% and 0.50%)and the matching V-101 vehicle cream in subjects with moderate to severeerythematous rosacea was conducted. There were 2 study visits. A totalof 85 subjects ranging in age from 27-84 years of age completed thetrial.

TABLE 20 Subject Demographics V-101 V-101 Vehicle 0.15% 0.50% TotalCharacteristic (N = 27) (N = 29) (N = 29) (N = 85) Age, years Mean (SD)52.3 (12.2) 46.6 (9.1) 50.6 (9.3) 49.8 (10.4) Range 27-84 33-72 33-7227-84 Gender, N Male 7 (25.9%) 5 (17.2%) 4 (13.8%) 16 (18.8%) Female 20(74.1%) 24 (82.8%) 24 (82.8%) 68 (80.0%) Missing 0 0 1 (3.4%) 1 (1.2%)Race, N White 27 (100%) 29 (100%) 29 (100%) 85 (100%) Other^(a) 0 0 0 0Ethnicity, N Hispanic or 1 (3.7%) 2 (6.9%) 3 (10.3%) 6 (7.1%) Latino NotHispanic or 26 (96.3%) 27 (93.1%) 26 (89.7%) 79 (92.9%) Latino Source:Section 14, Table 2

At Visit 1, subjects were screened and eligibility for randomization tostudy medication was determined during the period of up to 14 days priorto Visit 2. At Visit 2, subjects who were eligible were randomized tostudy medication (V-101 cream 0.15%, V-101 cream 0.50%, or vehicle creamin a 1:1:1 ratio). A single application of 0.5 g of study medication wasadministered and the subject was confined at the investigational centeruntil the end of the study evaluations (approximately 12.5 hours).

Pharmacodynamic evaluations were performed using the 5-point SSA scale,the 5-point CEA scale, and the 5-point Clinician's TelangiectasiaAssessment (CTA) scale. Safety was evaluated by treatment-emergentadverse events (TEAEs), laboratory evaluations, vital signs, andelectrocardiograms (ECGs).

Pharmacodynamics/Efficacy:

The primary endpoints of change-from-baseline CEA-AUC and SSA-AUC bothshowed statistically significant reductions in erythema for the 0.50%V-101 group compared with the vehicle group at all time pointsevaluated, from 3 to 12 hours post-application. The 0.15% V-101 groupshowed statistically significant reductions in erythema compared withthe vehicle group for CEA at all time points except 12 hours and for SSAat 6 and 8 hours. There was a consistent dose response between the V-101concentrations. The results were similar for treatment success rate. The0.50% V-101 group had a statistically significant higher overall successrate than the vehicle group from 3 to 8 hours post-application, withoverall treatment success defined as a score of <2 or a change fromvisit-day baseline of <−1 on the CEA and SSA. In the 0.50% V-101 groupthe overall treatment success rate increased from 17.24% at 3 hours to amaximum of 20.68% at 6 hours. In addition, the 0.50% V-101 groupdemonstrated statistically significant improvement in CTA compared tovehicle at all time points evaluated.

TABLE 21 Mean Change from Pre-dose as Area Under the Curve (AUC) forClinician's Erythema Assessment (CEA) and Subject's Self Assessment(SSA) Vehicle V-101 0.15% V-101 0.50% Variable (N = 27) (N = 29) (N =29) CEA-AUC Mean (SD) −3.241 (5.120) −8.155 (5.487) −14.552 (5.888)P-value^(a) — 0.000 0.000 SSA-AUC Mean (SD) −2.870 (3.999) −6.483(6.973)  −9.379 (5.730) P-value^(a) — 0.023 0.000 SD = standarddeviation ^(a)P-values were calculated by using an analysis ofcovariance based on baseline value and all variables were analyzed ascontinuous variables. Source: Section 14, Tables 9.9.1 and 9.9.2

TABLE 22 Clinician's Erythema Assessment: Baseline and Mean Change fromBaseline Mean (Standard Deviation) Vehicle V-101 0.15% V-101 0.50% Time(N = 27) (N = 29) (N = 29) Visit 2 Baseline  3.296 (0.465)  3.138(0.351)  3.241 (0.435) Post-application change  3 hours −0.519 (0.700)−1.069 (0.884)** −1.759 (0.786)**  4 hours −0.407 (0.694) −1.138(0.875)** −1.931 (0.704)**  6 hours −0.333 (0.620) −0.931 (0.799)**−1.690 (0.712)**  8 hours −0.296 (0.542) −0.655 (0.670)* −1.310(0.761)** 10 hours −0.148 (0.456) −0.448 (0.572)* −0.828 (0.658)** 12hours −0.037 (0.518) −0.241 (0.511) −0.483 (0.509)** Average hours−0.420 (0.603) −1.046 (0.722)** −1.793 (0.663)** 3-6 CEA scale: 0 =clear skin with no signs of erythema; 1 = almost clear, slight redness;2 = mild erythema, definite redness; 3 = moderate erythema, markedredness; 4 = severe erythema, fiery redness P-values were calculated byusing an analysis of covariance based on change from visit-day baselineat specified time points. Variables were analyzed as continuousvariables. *p < 0.05, **p < 0.01 Source: Section 14, Table 9.1

TABLE 22 Subject's Self-Assessment: Baseline and Mean Change fromBaseline Mean (Standard Deviation) Vehicle V-101 0.15% V-101 0.50% Time(N = 27) (N = 29) (N = 29) Visit 2 Baseline  3.222 (0.424)  3.276(0.455) 3.241 (0.435)  Post-application change 3 hours −0.296 (0.542)−0.586 (0.733) −0.828 (0.711)** 4 hours −0.333 (0.480) −0.621 (0.677)−1.034 (0.823)** 6 hours −0.259 (0.447)  −0.724 (0.797)* −0.966(0.680)** 8 hours −0.259 (0.447)  −0.655 (0.814)* −1.000 (0.707)** 10hours  −0.259 (0.526) −0.552 (0.736) −0.759 (0.689)** 12 hours  −0.222(0.577) −0.517 (0.785) −0.724 (0.649)** Average hours −0.296 (0.396) −0.644 (0.701)* −0.943 (0.661)** 3-6 SSA scale: 0 = clear of unwantedredness, 1 = nearly clear of unwanted redness, 2 = somewhat more rednessthan I prefer, 4 = completely unacceptable redness P-values werecalculated by using an analysis of covariance based on change fromvisit-day baseline at specified time points. Variables were analyzed ascontinuous variables. *p < 0.05, **p < 0.01 Source: Section 14, Table9.2

TABLE 23 Clinician's Telangiectasia Assessment: Baseline and Mean Changefrom Baseline Mean (Standard Deviation) Vehicle V-101 0.15% V-101 0.50%Time (N = 27) (N = 29) (N = 29) Visit 2 Baseline 2.074 (0.997) 1.931(0.842) 2.000 (1.102)  Post-application change 3 hours 0.185 (0.483)0.172 (0.658) −0.138 (0.516)*  4 hours 0.222 (0.424) 0.069 (0.371)−0.172 (0.468)** 6 hours 0.111 (0.424) 0.276 (0.455) −0.172 (0.468)*  8hours 0.185 (0.396) 0.207 (0.491) −0.172 (0.468)** 10 hours  0.148(0.362) 0.138 (0.441) −0.172 (0.468)** 12 hours  0.111 (0.424) 0.069(0.258) −0.103 (0.409)*  Average hours 0.173 (0.350) 0.172 (0.374)−0.161 (0.442)** 3-6 CTA scale: 0 = clear skin with no signs oftelangiectasia; 1 = almost clear, a few barely visible telangiectasia; 2= mild, a few visible telangiectasia; 3 = moderate, with the presence ofclearly visible telangiectasia; 4 = severe, with the presence of manyvisible telangiectasia P-values were calculated by using an analysis ofcovariance based on change from visit-day baseline at specified timepoints. Variables were analyzed as continuous variables. *p < 0.05, **p< 0.01 Source: Section 14, Table 9.3

In conclusion, the main objective of this single-dose study was toevaluate the safety and pharmacodynamic/efficacy profile of 0.15% and0.50% V-101 cream compared to vehicle cream applied to the face onsubjects with moderate to severe erythematous rosacea. Bothconcentrations showed statistically significant reductions in erythemacompared with the vehicle, starting at 3 hours post-application, whichwas the first time point evaluated. Statistically significant greaterimprovement with 0.50% V-101 cream compared to the vehicle wasmaintained through 12 hours post-application (the last time pointevaluated) for change from baseline in CEA and SSA and through 8 hourspost-application for overall treatment success. A clear dose responsewas demonstrated for all efficacy evaluations, with greater reductionsin erythema with 0.50% V-101 as assessed by all clinical indices.

It is of interest to note that a Although there was no entry criterionregarding CTA score and thus a wide variability in baseline scores(Section 14, Table 3), a significant improvement in CTA was seen with0.50% V-101 throughout the study.

Both concentrations of V-101 cream were well tolerated as assessed byTEAEs, clinical laboratory results, vital signs, and ECGs. There were nonotable differences between the concentrations in any of the safetyevaluations.

The present invention is not to be limited in scope by the specificembodiments disclosed in the examples which are intended asillustrations of a few aspects of the invention and any embodiments thatare functionally equivalent are within the scope of this invention.Indeed, various modifications of the invention in addition to thoseshown and described herein will become apparent to those skilled in therelevant art and are intended to fall within the scope of the appendedclaims.

A number of references have been cited, the entire disclosures of whichare incorporated herein in their entirety.

1. A method of treating two or more symptoms of rosacea selected fromerythema, telangiectasia, or inflammatory lesions comprising topicallyadministering a pharmaceutical composition comprising a therapeuticallyeffective amount oxymetazoline and a pharmaceutically acceptableexcipient.
 2. The method of claim 1, wherein the composition furthercomprises an additive selected from the group consisting of emulsifiers,preservatives, emulsion stabilizers, pH adjusters, chelating agents,viscosity modifiers, anti-oxidants, surfactants, emollients, opacifyingagents, skin conditioners, buffers, and combinations thereof.
 3. Themethod of claim 1, wherein the composition further comprises a topicallyactive pharmaceutical or cosmetic agent.
 4. The method of claim 1,wherein the oxymetazoline is in an amount of from about 0.0075% to about5% by weight.
 5. The method of claim 1, wherein the oxymetazoline is inan amount of from about 0.0075% to about 3% by weight.
 6. The method ofclaim 1, wherein oxymetazoline is in an amount from about 0.01% to about2.5% by weight.
 7. The method of claim 1, wherein oxymetazoline is in anamount from about 0.01% to about 2% by weight.
 8. The method of claim 1,wherein oxymetazoline is in an amount from about 0.01% to about 1% byweight.
 9. The method of claim 1, wherein oxymetazoline is in an amountfrom about 0.01% to about 0.5% by weight.
 10. The method of claim 1,wherein oxymetazoline is in an amount from about 0.01% to about 0.25% byweight.
 11. The method of claim 1, wherein oxymetazoline is in an amountfrom about 0.01% to about 0.15% by weight.
 12. The method of claim 1,wherein the therapeutic effect of the composition is maintained for atleast about 30 days after final administration of the composition.
 13. Amethod of treating a condition selected from the group consisting oferythema, telangiectasia, and inflammatory lesions associated withrosacea comprising topically administering a pharmaceutical compositioncomprising a therapeutically effective amount of oxymetazoline and apharmaceutically acceptable excipient.
 14. A method of treatingtelangiectasia comprising topically administering a pharmaceuticalcomposition comprising a therapeutically effective amount ofoxymetazoline and a pharmaceutically acceptable excipient.
 15. A methodof treating inflammatory lesions comprising topically administering apharmaceutical composition comprising a therapeutically effective amountof oxymetazoline and a pharmaceutically acceptable excipient.